Acid addition salts of piperazine derivatives

ABSTRACT

The invention relates to acid addition salts of piperazine derivatives, as well as solid forms, such as polymorphic forms, thereof, which are useful as pharmaceutical ingredients and, in particular, as glycosidase inhibitors.

RELATED APPLICATIONS

This application is a U.S. National Phase application, filed under 35U.S.C. § 371(c), of International Application No. PCT/EP2017/054278,filed Feb. 24, 2017, which claims priority to, and the benefit of,Indian Patent Application No. 201621006638, filed Feb. 25, 2016, each ofwhich is incorporated by reference herein in its entirety for allpurposes.

FIELD OF THE INVENTION

The invention relates to acid addition salts of hydrochloric acid,maleic acid or tartaric acid or other acids with piperazine derivatives,as well as solid forms, such as polymorphic forms, thereof, which areuseful as pharmaceutical ingredients and in particular as glycosidaseinhibitors.

BACKGROUND OF THE INVENTION

Piperazine derivatives of formula I

wherein X, n and Q are as defined further below, are as pharmaceuticalingredients and show high activity as glycosidase inhibitors. Forexample, PCT/EP2015/069598 describes e.g.N-(5-{4-[(1S)-1-(2,3-dihydro-1-benzofuran-6-yl)ethyl]piperazin-1-yl}-1,3,4-thiadiazol-2-yl)acetamideandN-(2-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}pyrimidin-5-yl)acetamideas active glycosidase inhibitors having high inhibitory activities.

Although the compounds of formula I have very useful pharmaceuticalactivities as free piperazine bases, they are not ideal forpharmaceutical manufacturing and as such may not be suitable for certaindosage forms, especially oral dosage forms, due to their unfavorabledissolution behaviour and stability or reactivity and other propertiesin the solid state.

Thus, there is a need to provide improved solid forms comprising thecompounds of formula I, which exhibit improved properties, can be easilymanufactured into solid dosage forms or other pharmaceutical dosageforms, and show an improved dissolution behaviour and stability and/orare less reactive in the solid state.

SUMMARY OF THE INVENTION

It has now been found that compounds of formula I

wherein X, n and Q are as defined further below show improved solidstate properties, after they have been transformed in acid additionssalts of hydrochloride acid, maleic acid or tartaric acid or otheracids. In particular, the acid addition salts can be easily manufacturedinto solid dosage forms or other pharmaceutical dosage forms, and showan improved dissolution behavior and stability and/or are less reactivein the solid state. The acid addition salts of the present inventionoften exhibit low hygroscopicity.

It has also been found that certain polymorphic forms of the acidaddition salts show even further improved properties, making them idealfor pharmaceutical manufacturing, in particular for solid oral dosageforms. Moreover, acid addition salts of the present invention that havea molar ratio of the compounds of formula I to the respective acid of 1to 1 are especially stable, soluble and/or show other improvedproperties.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to acid addition salts of hydrochloric acid,maleic acid or tartaric acid or other acids with compounds of formula I

whereinX denotes O or CH₂,n denotes 0 or 1,andQ denotes one of the following groups:

-   -   Z¹ is S, O, NR³;    -   Z², Z^(2′), Z³ independently denote CR⁵, CR⁶ or N;    -   R³, R⁴ denote each independently H or a straight chain or        branched alkyl group having 1 to 12 carbon atoms;    -   R⁵, R^(5′), R⁶, R⁷ independently denote H, Hal, NR³R⁴, NO₂,        straight chain or branched alkyl having 1 to 12 carbon atoms,        wherein 1 to 3 CH₂-groups may be replaced by a group selected        from O, NR³, S, SO, SO₂, CO, COO, OCO, CONR³, NR³CO and wherein        1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴, NO₂, OR³,        Het, Ar, Cyc, or denote Ar, Het or Cyc;    -   R⁸ denotes H, methyl or straight chain or branched alkyl having        2 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced        by a group selected from O, NR³, S, SO, SO₂, CO, COO, OCO,        CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may be replaced        by Hal, NR³R⁴ or NO₂;    -   Hal denotes F, Cl, Br or I;    -   Het denotes a saturated, unsaturated or aromatic ring, being        monocyclic or bicyclic or fused-bicyclic and having 3- to        8-members and containing 1 to 4 heteroatoms selected from N, O        and S, which may be substituted by 1 to 3 substituents selected        from R⁵, Hal and OR³;    -   Ar denotes a 6-membered carbocyclic aromatic ring or a fused or        non fused bicyclic aromatic ring system, which is optionally        substituted by 1 to 3 substituents independently selected from        R⁵, OR³ and Hal;    -   Cyc denotes a saturated or an unsaturated carbocyclic ring        having from 3 to 8 carbon atoms which is optionally substituted        by 1 to 3 substituents independently selected from R⁵ or Hal or        OH,        as well as solid forms, such as solvates and polymorphic forms        thereof.

Polymorphism describes the occurrence of different solid or crystallineforms of a single compound and it is a property of certain compounds andcomplexes. Thus, polymorphs or polymorphic forms are distinct solidssharing the same molecular formula, yet each polymorph or polymorphicform may have distinct physical properties. Therefore, a single compoundmay give rise to a variety of polymorphic forms where each form hasdifferent and distinct physical properties, such as different solubilityprofiles, different melting point temperatures and/or different x-raydiffraction peaks.

The occurrence of a polymorphic form may determined by thecrystallization conditions such as choice of solvent(s), rate of solventaddition, temperature, stirring rate, level of super-saturation, andlevel of impurities. Hence, different crystallization processes may giverise to different polymorphs. Polymorphs also have different stabilitiesand may spontaneously convert from one form to another.

The unpredictability of polymorphism, both as regards the uncertaintythat any forms could be found, and the lack of any standard methods forpreparing a new form has e.g. been discussed in A. Goho, “TrickyBusiness,” Science News, Vol. 166(8), Aug. 21, 2004, and A. M. Rouhi,“The Right Stuff,” Chemical and Engineering News, Feb. 24, 2003, pages32-35.

Polymorphs can be distinguished from each other by a variety ofanalytical techniques. Polymorphs exhibit distinct spectroscopicproperties and can be identified using infrared spectroscopy, ramanspectroscopy, and 13C-NMR spectroscopy. Due to the fact that eachcrystal form diffracts X-rays in different ways, X-ray powderdiffractometry (XRPD) can also be used for identification. Furthermore,thermal methods such as differential scanning calorimetry (DSC) andthermogravimetric 5 analysis (TGA) can provide information unique to aparticular polymorph. The polymorphic forms of a compound can be also bedistinguished by other methods such as, infrared spectrometry. For ageneral review of polymorphs and the pharmaceutical applications ofpolymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986); J. Haleblian andW. McCrone, J. Pharm. Sci., 58, 91 1 (1969); and J. Haleblian, J. Pharm.Sci., 64, 1269 (1975).

The physicochemical properties may vary strongly between individualpolymorphic forms. For example, solubility and dissolution rate may varybetween polymorphs, leading to potential differences in bioavailability.Furthermore, mechanical properties such as flowability andcompactability, which affect the processing properties of a compound,may be different. Stability, vapor impermeability and shelf life of acompound may also depend on the chosen polymorph.

The polymorphic forms, including solvates of the present inventionprovide materials having desirable processing properties, such as easeof handling, ease of processing, storage stability, and ease ofpurification, or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms with improved properties. Moreoverthe invention provides and stable forms of drug substances, whichpreferably exhibit thermodynamic stability, enhanced solubility, rapidonset of action and an enhanced bioavailability. The acid addition saltsof the present invention are improved at least in one of theaforementioned properties.

In a preferred embodiment, the invention relates to the acid additionsalts of compounds of formula Ia

wherein Q has the meaning given above and solid forms, such as solvatesand polymorphic forms, thereof.

More preferably the invention relates to acid addition salts ofcompounds of formula Ia, wherein Q is selected from the group

wherein R⁵, R^(5′), R⁷ and R⁸ have the meaning given above.

In a preferred embodiment, the invention relates to acid addition saltsof compounds of formula I or Ia, wherein R⁵, R^(5′), R⁶, R⁷ areindependently H, Hal, NR₃R₄, NH₂, N(CH₃)₂, phenyl, 2-, 3- or 4-hydroxyor methoxyphenyl, alkyl, CF₃, alkoxy (Oalkyl), hydroxyalkylen,alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH₂, CON(CH₃)₂, NHCOalkyl,NHalkyl, CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N— morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, substituted orunsubstituted Cyc or Het,

as well as solid forms, such as polymorphic forms, thereof.

Very preferred are the acid additions salts, as well as solid forms,such as polymorphic forms thereof, of compounds of formula I, wherein Qis selected from the group:

Very preferred are also the acid additions salts, as well as solidforms, such as polymorphic forms thereof, of the following compounds:

The compounds of formula I are usually employed in an enantiomericexcess, as measured by methods well known by one skilled in the art, of10% or more, preferably 50% or more, and more preferably more than 95%,96%, 98% or 99%.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The compounds of invention have been named according to thestandards used in the program AutoNom 2000 or ACD Lab Version 12.01. Theterms indicated for explanation of the above compounds of the inventionalways, unless indicated otherwise in the description or in the claims,have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituentthe expression of such substituent may differ from each other (e.g.methyl and ethyl). It shall be understood accordingly that a multiplesubstitution by any radical of the invention may involve identical ordifferent radicals. Hence, if individual radicals occur several timeswithin a compound, the radicals adopt the meanings indicated,independently of one another.

The term “alkyl” or “alkyl group” refers to acyclic saturated orunsaturated hydrocarbon radicals, which may be branched orstraight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, i.e. C₁-C₁₀-alkanyls. Examples of suitable alkyl radicalsare methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,

n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl,n-icosanyl, n-docosanyl.

In an embodiment of the invention, alkyl denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7 H atoms may be replacedindependently from one another by Hal. A preferred embodiment of alkyldenotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4atoms may be replaced independently from one another by Hal. In a morepreferred embodiment of the invention, alkyl denotes unbranched orbranched alkyl having 1-4 C atoms, in which 1-3 H atoms can be replacedindependently from one another by Hal, particularly by F and/or Cl. Itis most preferred that alkyl denotes unbranched or branched alkyl having1-6 C atoms. Highly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of alkyl is independently of one another inany radical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s). The bonding to the compounds of the general formula (I) canbe effected via any possible ring member of the cycloalkyl radical.Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclohexenyl, cyclopentenyl and cyclooctadienyl.

In an embodiment of the invention, Cyc denotes cycloalkyl having 3-7 Catoms, in which 1-4 H atoms may be replaced independently of one anotherby Hal. Preferred is C₃-C₇-cycloalkyl. More preferred isC₄-C₇-cycloalkyl. Most preferred is C₅-C₇-cycloalkyl, i.e. cyclopentyl,cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “Ar” “aryl” or “carboaryl” for the purposes of this inventionrefers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to14, preferably 3-12, more preferably 4 to 12, most preferably 5 to 10,highly preferably 6 to 8 carbon atoms, which can be optionallysubstituted. The term “aryl” also includes systems in which the aromaticcycle is part of a bi- or polycyclic saturated, partially unsaturatedand/or aromatic system, such as where the aromatic cycle is fused to anaryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein viaany desired and possible ring member of the aryl radical. The bonding tothe compounds of the general formula (I) can be effected via anypossible ring member of the aryl radical. Examples of suited arylradicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl andanthracenyl, but likewise indanyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocyclic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

Aryl is preferably selected from the following group: phenyl, o-, m- orp-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- orp-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- orp-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- orp-(N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-dimethyl-sulfonamido)-phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Irrespective of further substitutions, Het denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazoM-, -4- or -5-yl, 1,2,4-triazo-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-5i-ndolyl, indazolyl, 1-, 2-,4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl. The heterocyclic radicals mayalso be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-di-hydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-(-2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetra-hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-di-hydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl,4-methylpiperazinyl, pyrrolidinyl, morpholinyl, dihydro-pyrazolyl,dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, indolyl, benzo-1,3-dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or benzothiadiazolyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It shall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

Preferred acids for the preparation of the acid addition salts arehydrochloric acid, maleic acid or tartaric acid, especially hydrochloricacid. Other pharmaceutically suitable acids, especially strong acids,such as sulfuric acid or p-toluene sulphonic acid may also be usedaccording to the invention.

Acid addition salts of the present invention can be obtained indifferent molar ratios. Due to the presence of at least the two nitrogenatoms in the piperazine moiety of the compound of formula I, the acidaddition salts can be prepared in a 1 to 1 molar ratio or in a 1 to 2molar ratio for the compounds of formula I to an acid having a oneacidic proton. This usually also holds true in cases where the acid hasmore than one acidic proton, as the second or further protons aresignificantly less acid than the one of the first deprotonation step. Ithas been found that the acid addition salts of the present inventionthat have a molar ratio of the compounds of formula I to the respectiveacid of 1 to 1 are especially preferred and stable, soluble and/or showother improved properties.

The acid addition salts of hydrochloric acid with compounds of formula Iand solid forms, such as solvates and polymorphic forms thereof, arevery preferred. Most preferred are acid addition salts of hydrochloricacid with compounds of formula I and solid forms, such as solvates andpolymorphic forms thereof, wherein the molar ratio of the compound offormula I to hydrochloric acid is 1 to 1.

A preferred method of preparation of the acid addition salts ofcompounds of formula I according to the invention comprises thefollowing steps:

a) suspending or dissolving the compound of formula I and the selectedacid in a suitable solvent or solvent mixture;

b) heating the mixture obtained in step a) to a temperature of betweenabout 30° C. to about the boiling point of the selected solvent,preferably between about 50° C. and about 100° C. and most preferably toabout 60° C., to about 70° C. or to about 80° C. and allowing themixture to cool to room temperature;c) optionally repeating step b) several times;d) separating and drying the solid thus obtained.

Suitable solvents for the method of preparation of the acid additionsalts of the present invention are preferably alcohols such as water,methanol (MeOH, ethanol, 1-propanol, 2-propanol (IPA), 1-butanol,2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol,3-methyl-1-butanol, 2,2-dimethyl-1-propanol, cyclopentanol, 1-hexanol,cyclohexanol, 1-heptanol, 1-octanol, 1-nonanol, 1-decanol,2-propen-1-ol, ketones, such as acetone, esters, such as ethyl acetate,acetonitrile, ethers such as tetrahydrofurane (THF), aromatichydrocarbons, such as toluene and homogeneous mixtures of the abovesolvents, such as MeOH/water e.g. as 50/50 (v/v) mixture or IPA/water,e.g. as 90/10 (v/v) mixture.

Pharmaceutical formulations can be administered in the form of dosageunits, which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the acid addition salts of the compounds offormula I or the pharmaceutically are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit, calculated on the respectivebase. Generally, such a dose range is appropriate for total dailyincorporation. In other terms, the daily dose is preferably betweenapproximately 0.02 and 100 mg/kg of body weight.

Preferably the daily dose, i.e. the sum of all doses given to a patientduring a given day, of a compound of formulaN-(5-{4-[(1S)-1-(2,3-dihydro-1-benzofuran-6-yl)ethyl]piperazin-1-yl}-1,3,4-thiadiazol-2-yl)acetamide,N-(5-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}-1,3,4-thiadiazol-2-yl)acetamide,2-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}-N-methyl-1,3-thiazole-5-carboxamide,2-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}-N-methylpyrimidine-5-carboxamide,N-(2-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}pyrimidin-5-yl)acetamide,2-{4-[(1S)-1-(2,3-dihydro-1-benzofuran-6-yl)ethyl]piperazin-1-yl}-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridin-4-oneis between about 20 and about 100 mg, more preferably between about 30mg and 70 mg calculated on the respective base, such as about 30, 35 or40 mg given twice daily, preferably orally adminstered. The compoundsare preferably administered in form of their hydrochloride salt,especially that having a molar ratio of the respective compound tohydrochloric acid of 1 to 1. The acid addition salts of the presentinvention are preferably orally administered.

The following embodiments are related to the use of the acid additionsalts of the invention:

-   1. Acid addition salts according to the invention for use in a    treatment of a condition selected from neurodegenerative diseases,    diabetes, cancer, cardiovascular diseases and stroke.-   2. Acid addition salts according to embodiment 1 for use in a    treatment of a condition according to claim 10, wherein the    condition is selected from the group of one or more tauopathies and    Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis (ALS),    Amyotrophic lateral sclerosis with cognitive impairment (ALSci),    Argyrophilic grain disease, Behavioural variant frontomeporal    dmenetia (BvFTD), Bluit disease, Chronic traumatic encephalopathy,    Corticobasal degeneration (CBP), Dementia pugilistica, Diffuse    neurofibrillary tangles with calcification, Down's syndrome,    Familial British dementia, Familial Danish dementia, Frontotemporal    dementia with parkinsonism linked to chromosome 17 (FTDP-17),    Frontotemporal lobar degeneration (FTLD), Ganglioglioma,    Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glia    tauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease    (neurodegeneration with brain iron accumulation type 1), Lead    encephalopathy, Lipofuscinosis, Meningioangiomatosis, Multiple    system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C),    Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of    Guam, Pick's disease (PiD), Parkinson's disease dementia,    Postencephalitic parkinsonism (PEP), Primary progressive aphasia,    Prion diseases (including Creutzfeldt-Jakob Disease (GJD),    Progressive nonfluent aphasia, Variant Creutzfeldt-Jakob Disease    (vCJD), Fatal Familial Insomnia, Kuru, Progressive supercortical    gliosis, Progressive supranuclear palsy (PSP), Semantic dementia,    Steele-Richardson-Olszewski syndrome, Subacute sclerosing    panencephalitis, Tangle-only dementia, Tuberous sclerosis,    Huntington's disease and Parkinson's disease, preferably one or more    tauopathies and Alzheimer's disease.-   3. A method for treating a tauopathy, wherein an acid addition salt    according to the invention is administered to a mammal in need of    such treatment.-   4. A method for inhibiting a glycosidase, wherein a system    expressing the glycosidase is contacted with an acid addition salt    of hydrochloric acid, maleic acid or tartaric acid with acid    addition salt according the invention under in-vitro conditions such    that the glycosidase is inhibited.    Preparation of Compounds of Formula I

Preferred forms of the acid addition salts of the present inventiondemonstrate adequate properties for use as a drug. In particular suchpreferred compounds show a high solid state stability, high stability inthe presence of liver microsome, high oxidation stability and suitablepermeability. Further preferred compounds of the present inventiondemonstrate their suitability as drugs by potent biological activity,such as the level of O-GlcNAcylation of total proteins measured in brainextracts. Relevant tests for determining such parameters are known bythe person skilled in the art, e.g. solid state stability (Waterman K.C. (2007) Pharm Res 24(4); 780-790), stability in the presence of livermicrosome (Obach R. S. (1999) Drug Metab Dispos 27(11); 1350-135) andthe permeability (e.g. Caco-2 permeability assay, Calcagno A. M. (2006)Mol Pharm 3(1); 87-93); alternatively, they are described in Examplesbelow, such as Example B02 describing the determination ofO-GlcNAcylation level of total proteins measured in brain extracts.Compounds of the present invention that show a high potency in OGAinhibition assays and one or more of the above properties are especiallysuitable as a drug for the indications mentioned in the presentspecification.

The compounds according to formula (I) and the starting materials forits preparation, respectively, are produced by methods known per se, asdescribed in the literature, i.e. under reaction conditions that areknown and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The following abbreviations refer respectively to the definitions below:

Ac (acetyl), aq (aqueous), h (hour), g (gram), L (liter), mg(milligram), MHz (Megahertz), μM (micromolar), min (minute), mm(millimeter), mmol (millimole), mM (millimolar), m.p. (melting point),equiv (equivalent), mL (milliliter), μL (microliter), ACN(acetonitrile), AcOH (acetic acid), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene, BOC(tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),dppf (1,1′-bis(diphenylphosphino)ferrocene), DIC (diisopropylcarbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide),DMSO (dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (Ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MD Autoprep (Mass directed Autoprep), MeOH (methanol),MgSO₄ (magnesium sulfate), MS (mass spectrometry), MTBE (Methyltert-butyl ether), Mtr. (4-Methoxy-2, 3, 6-trimethylbenzensulfonyl), MW(microwave), NBS (N-bromo succinimide), NaHCO₃ (sodium bicarbonate),NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR (NuclearMagnetic Resonance), POA (phenoxyacetate), Py (pyridine), PyBOP®(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SFC(supercritical fluid chromatography), SPE (solid phase extraction), T3P(propylphosphonic anhydride), TBAF (tetra-n-butylammonium fluoride),TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofurane), TLC (Thin Layer Chromatography), UV (Ultraviolet).

In general, the compounds according to Formula (I) and related formulaeof this invention may be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those having ordinary skillin the art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

A “leaving group” LG denotes a chemical moiety which can be removed orreplaced by another chemical group. Throughout the specification, theterm leaving group preferably denotes Cl, Br, I or a reactively modifiedOH group, such as, for example, an activated ester, an imidazolide oralkylsulfonyloxy having 1 to 6 carbon atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).When a leaving group LG is attached to an aromatic or heteroaromaticring, LG can denote in addition SO₂-alkyl or F. Radicals of this typefor activation of the carboxyl group in typical acylation reactions aredescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters areadvantageously formed in situ, for example through addition of HOBt,N-hydroxysuccinimide or HATU.

Depending on the nature of the groups such as Q, different syntheticstrategies may be selected for the synthesis of compounds of Formula(I). In the process illustrated in the following schemes, X, n and Q areas above-defined in the description unless otherwise mentioned.

Compounds of Formula (I), wherein X, n and Q are defined as above, canbe prepared from alternative compounds of Formula (I), using suitableinterconversion procedures such as those described hereinafter in theexamples, or conventional interconversion procedures well known by oneskilled in the art.

Compound of formula (I) can be separated its corresponding otherenantiomer by chiral chromatography or by chiral resolution,re-crystallization with use of an optically active acid.

Preferred chiral acids used for the chiral resolution of compounds offormula I and Ia are selected from but not limited to (S)-Me-mandelicacid, (S)-4-bromo-mandelic acid, (S)-4-chloro-mandelic acid,(S)-phenylsuccinic acid. These acids are preferably employed, as theS-enantiomer of the respective compound of formula I is desired and thediastereomeric salts are crystallizing. Preferably, between about 0.5and about 2 equivalents of chiral acid are used for the selectivecrystallization. Solvents and solvent mixtures that are preferably usedfor the chiral resolution with chiral acids, are H₂O, MeCN(Acetonitril), about 2 to about 50% H₂O in EtOH (Ethanol), EtOH, 2 to50% H₂O in MeOH (methanol), MeOH, 2 to 50% H₂O in IPA (isopropylalcohol), IPA, 2 to 50% MeOH in MEK (methyl ethyl ketone, 2-butanone),MEK, 2 to 50% MeOH in iPrOAc (isopropyl acetate), iPrOAc, dioxane. Allpercentages for solvent mixtures are given in volume percent, if notindicated otherwise.

Preferably, methods known by one skilled in the art are used in thepreparation. Further methods of preparation are as described below inthe examples.

Compounds of formula (Ic), wherein A is

R is methyl and Q are defined as above, can be prepared by the additionof an amine of formula (II) to a heterocycle of formula (III), where LGis a leaving group as defined above. This addition can be performedunder thermic conditions, heating both compounds at a temperaturebetween 50° C. and 200° C., using regular heating or microwaveirradiation, in the presence of a base, such as but not limited to TEA,DIEA, K₂CO₃ or Cs₂CO₃, in a polar solvent, e.g. DMF, DMA or NMP.Alternatively, this addition can be catalysed by a metal complex, suchas but not limited to PdCl₂, Pd(OAc)₂, Pd₂(dba)₃ in the presence of aligand, e.g. BINAP, o-Tol₃P, X-Phos, and a base, e.g. NaOtBu, Cs₂CO₃ orK₂CO₃, in a suitable solvent or solvent mixture, for example dioxane,Toluene/MeOH, at a temperature between RT to 150° C., preferably at RT,for a few hours, e.g. one hour to 24 h (Scheme 1). Amine of formula (II)is obtained after deprotection of compound (IVa). PG is a suitableprotecting group, which is compatible with the chemistry describedbelow, such as but not limited to BOC. It can be removed under acidicconditions, such as but not limited to HCl in MeOH or dioxane or TFA inDCM, yielding isolation of amine (II).

Compound of formula (IV), wherein A, R and Q are defined as above and Y¹is a protecting group PG, can be prepared from the corresponding ketone(IX) by reductive amination with amine (VI), using conditions known tothe one skilled in the art, such as but not limited to the use ofNaBH(OAc)₃ as reducing agent, in the presence of one equivalent of AcOHin DCE. Alternatively, reductive amination can be performed in twosteps, with first imine formation, that can be catalysed by Ti(OiPr)₄,followed by reduction with suitable reducing agent, such as but notlimited to NaBH₄ in MeOH (Abdel-Magid, A. F. at al. J. Org. Chem. 1996,61, 3849-3862). Alternatively, ketone (IX) can be reduced into thecorresponding alcohol (VIII) using usual reductive agents such as NaBH₄in an alcoholic solvent, such as MeOH. Alcohol functionality can be thentransformed into a suitable leaving group, such as but not limited to Clor OMs, using conditions known to a person skilled in the art. Theaddition of amine (VI) to intermediate (VII) would yield the formationof compound (IV) (Scheme 2).

Alternatively, compound of formula (X), wherein Q are defined as aboveand PG is a suitable protecting group, such as but not limited to BOC,can be prepared from amine (XI) (Scheme 3).

Compound of formula (X) can be prepared by the addition of an amine offormula (XI) to a heterocycle of formula (III), where LG is a leavinggroup as defined above. This addition can be performed under thermicconditions or can be catalysed by a metal complex, using conditionsknown by a person skilled in the art and as described below in theexamples.

PG is a suitable protecting group, which is compatible with thechemistry described above, such as but not limited to BOC. It can beremoved under acidic conditions, such as but not limited to HCl in MeOHor dioxane or TFA in DCM, yielding isolation of amine (XIV). It can befurther transformed into compound of formula (I) by reductive alkylationwith ketone of formula (IX), following conditions well known by a personskilled in the art, as described in the examples (Abdel-Magid, A. F. atal. J. Org. Chem. 1996, 61, 3849-3862). Alternatively, amine (XIV)addition to compound (VII), prepared as described above and in theexamples, would yield the formation of compound of formula (I) afterchiral resolution.

Amine of formula (II) can be separated into amines of formula (IIa) and(IIb) by chiral chromatography or chiral resolution byre-crystallization with an optically active acid, using methods known byone skilled in the art and as described below in the examples (Scheme5).

Alternatively, amines of formula (IIa) and (IIb) can be synthesized fromchiral amines (XVIa) and (XVIb) respectively according to Scheme 6.Addition of amines (XVIa) and (XVIb) to reagent (XV), wherein PG is aprotecting group, e.g. BOC or SO₂Tol and LG is a leaving group, e.g. Cl,would yield the formation of protected amines (IVe) and (IVf)respectively (Thiel, O. R. et al. J. Org. Chem. 2008, 73, 3508-3515).Deprotection conditions need to be selected based on the nature of thePG, such as HCl in dioxane or MeOH or TFA in DCM for BOC protectinggroup. Alternatively a mixture of HBr, AcOH and 4-hydroxybenzoic acid ora mixture of H₂SO₄ and trifluoroacetic acid at temperatures ranging fromRT to 100° C. would be used to cleave a sulfonamide protecting group,such as para-toluene sulfonamide.

For the preparation of amines of formula (XVIa) and (XVIb), ketone offormula (IX) can be transformed into chiral imine (XVIII) according toScheme 7, reacting with a chiral auxiliary, such as but not limited totert-butanesulfinamide group in the presence of titanium ethoxide(Ellman J. A. et al. Acc. Chem. Res. 2002, 35, 984-995). It can befurther transformed into sulfinamide (XVIIa) or (XVIIb), depending onthe conditions used for the reduction step, as described in thereference from Ellman J. A. et al. J. Org. Chem. 2007, 72, 626-629.

Alternatively aldehyde of formula (XIX) can be transformed into alcoholof formula (VIII) with addition of a suitable nucleophile, such as butnot limited to a Grignard reagent (Scheme 8).

In another process, ketone of formula (IXa) can be obtained by Stillecross coupling reaction between aryl halide (XX) andtributyl(1-ethoxyvinyl)tin in the presence of a catalyst, such as butnot limited to Pd(PPh₃)₂Cl₂ in toluene at temperatures ranging from RTto 110° C. (Scheme 9).

When a reaction is preferably performed under basic conditions, asuitable base might be selected from metal oxides, e.g. aluminum oxide,alkaline metal hydroxide (potassium hydroxide, sodium hydroxide andlithium hydroxide, inter alia), alkaline earth metal hydroxide (bariumhydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates(potassium ethanolate and sodium propanolate, inter alia), alkalinemetal carbonates (e.g., sodium bicarbonate) and several organic bases(e.g., N,N-diisopropylethylamine, piperidine or diethanolamine, interalia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to TFA, DMF,dichloromethane, THF, H₂O, methanol, tert. butanol, tert. amylalcohol,triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −80° C.and 140° C., normally between −50° C. and 120° C., preferably between−20° C. and 100° C.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further illustrated by reference to theaccompanying figures:

FIG. 1: Characteristic X-ray powder diffraction pattern of crystallineExample 69 sulphate salt obtained in THF

FIG. 2: Characteristic X-ray powder diffraction pattern of crystallineExample 69 maleate salts obtained in ethanol, acetone, ethyl acetate

FIG. 3: Characteristic X-ray powder diffraction pattern of crystallineExample 69 maleate salt obtained in MeCN

FIG. 4: Characteristic X-ray powder diffraction pattern of crystallineExample 69 fumarate salt obtained in alcohol/water mixtures

FIG. 5: Characteristic X-ray powder diffraction pattern of crystallineExample 69 L-tartrate salts obtained in ethanol, acetone, MeCN, THF,methanol/water

FIG. 6: Characteristic X-ray powder diffraction pattern of crystallineExample 69 Tosylate salts obtained in acetone, MeCN

FIG. 7: Characteristic X-ray powder diffraction pattern of crystallineExample 69 free base

FIG. 8: Characteristic Raman spectrum of crystalline Example 69 freebase

FIG. 9: Characteristic STA thermogram of crystalline Example 69 freebase

FIG. 10: Characteristic DSC thermogram of crystalline Example 69 freebase

FIG. 11: Characteristic X-ray powder diffraction pattern of crystallineExample 69 hydrochloride salt

FIG. 12: Characteristic Raman spectrum of crystalline Example 69hydrochloride salt

FIG. 13: Characteristic NMR spectrum of crystalline Example 69hydrochloride salt

FIG. 14: Characteristic STA thermogram of crystalline Example 69hydrochloride salt

FIG. 15: Characteristic DSC thermogram of crystalline Example 69hydrochloride salt

FIG. 16: Characteristic X-ray powder diffraction pattern of crystallineExample 69 maleate salt obtained from EtOH

FIG. 17: Characteristic NMR spectrum of crystalline Example 69 maleatesalt obtained from EtOH

FIG. 18: Characteristic STA thermogram of crystalline Example 69 maleatesalt obtained from EtOH

FIG. 19: Characteristic DSC thermogram of crystalline Example 69 maleatesalt obtained from EtOH

FIG. 20: Characteristic X-ray powder diffraction pattern of crystallineExample 69 L-tartrate salt

FIG. 21: Characteristic NMR spectrum of crystalline Example 69L-tartrate salt

EXAMPLES

The compounds according to Formula (I) can be prepared from readilyavailable starting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples. All reported yields are non optimized yields.Unless otherwise stated, compounds of Formula (I) and related formulaeobtained as a racemic mixture can be separated to provide anenantiomerically enriched mixture or a pure enantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Sigma, ACROS,ABCR, Combi-Blocks, Matrix, Apollo scientific, Alfa Aesar, etc. unlessotherwise reported.

The HPLC, MS and NMR data provided in the examples described below areobtained as followed:

¹H NMR analyses were carried out using BRUKER NMR, model AV-II andAV-III 400 MHz FT-NMR. Residual signal of deuterated solvent was used asinternal reference. Chemical shifts (δ) are reported in ppm in relativeto the residual solvent signal (δ=2.50 for ¹H NMR in DMSO-d₆, and 7.26in CDCl₃). s (singlet), d (doublet), t (triplet), q (quadruplet), br(broad), quint (quintuplet).

The MS data provided in the examples described below were obtained asfollowed: Mass spectrum: LC/MS Agilent (ESI/APCI), Chemstration, 1200Series.

LCMS Methods:

Method A

Method: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm+ve mode

Method B

Method: A—10 mM NH₄HCO₃ in H₂O, B-ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

Method C

Method: A—10 mM NH₄HCO₃ in H₂O, B-ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), −ve mode

HPLC analyses were obtained using Agilent 1200 Series instruments asfollowed using % with UV detection (maxplot).

Method A

Method: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method B

Method: A—10 mM NH₄HCO₃ in H₂O, B-ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method C

Method: Gradient from 70% H₂O (10 mM K₂HPO₄): 30% MeCN to 70% MeCN over15 minutes, Flow: 1 mL/min. Column: XTERRA RP18 (250×4.6) mm, 5 μm

Chiral HPLC

Method A

Mobile Phase: 0.1% DEA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALPAK AD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Method B:

Mobile Phase: n-HEXANE:EtOH: 90:10: FLOW: 1.0 mL\min; COLUMN: CHIRALPAKIC (250×4.6) mm, 5 μm

Method C:

Mobile Phase: 0.1% TFA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALcell OD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Method D:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN:Chiralcell OJ-H column (250×4.6) mm, 5 μm

Method E:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN:Chiralcell AY-H column (250×4.6) mm, 5 μm

Method F:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 1.0 mL\min; COLUMN:Chiralpak IA (250×4.6) mm, 5 μm

Method G:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 60:40; FLOW: 1.0 mL\min; COLUMN:Chiralcel OD-H (250×4.6) mm, 5 μm

Method H:

Mobile Phase: 0.1% DEA in n-Hexane:EtOH: 80:20; FLOW: 1.0 mL\min;COLUMN: CHIRALPAK IC (250×4.6) mm, 5 μm

General flash chromatography conditions used for the purification ofintermediates or compounds of Formula I: silica gel 230-400 mesh;gradients used as eluent: 10 to 80% EtOAc in Petroleum ether or 1 to 15%MeOH in DCM

MD Autoprep Conditions

The mass directed preparative HPLC purifications were performed with amass directed autopurification Fractionlynx from Waters.

Method A

0.1% HCOOH in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7μm

Method B

0.1% TFA in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

Method C

10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

Method D

10 mM NH₄OAC in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

Preparative HPLC Conditions

Method PA

0.1% TFA in H₂O, B-MeOH or ACN. Column: Sunfire C8 (19 mm×250 mm) 5 μmor Sunfire C18 (30 mm×250 mm) 10 μm.

Method PB

10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Sunfire C8 (19 mm×250 mm) 5μm or Sunfire C18 (30 mm×250 mm) 10 μm.

Chiral Preparative Method PC

Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PD:

Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PE:

Mobile phase: n-Hexane, IPA; Column: Chiralcell OD-H (20×250) mm, 5micron, Flow: 12 mL/min

Chiral Preparative Method PF:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN:Chiralcell OJ-H column (250×20) mm, 5 μm

Chiral Preparative Method PG:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 20.0 mL\min; COLUMN:Chiralcell AY-H column (250×30) mm, 5 μm

Chiral Preparative Method PH:

Mobile Phase: n-HEXANE:ETOH: 90:10: FLOW: 20.0 mL\min; COLUMN: CHIRALPAKIC (250×30) mm, 5 μm

Chiral Preparative Method PI:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN:Lux Cellulose C4 (250×21.2) mm, 5 μm

Chiral Preparative Method PJ:

Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 12.0 mL\min; COLUMN:Chiralpak IA (250×20) mm, 5 μm

Chiral Preparative Method PK:

Mobile Phase: 0.1% DEA In Hexane:EtOH: 50:50; FLOW: 10.0 mL/min; COLUMN:Chiralpac IC (250×21) mm, 5 μm

The SFC purifications were performed with a Prep SFC, THAR-SFC 80 andTHAR-SFC 200.

SFC Analytical Chiral Method AA:

COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol 40%; FLOW: 4 mL/min;

SFC Preparative Chiral Method PA:

COLUMN: YMC Cellulose SB (250×30) mm, 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol 40%; FLOW: 60 mL/min;

The microwave chemistry was performed on a single mode microwave reactorInitiator™ Sixty from Biotage.

General Procedure for Ester Reduction of Heterocycles: Procedure A

To a stirred solution of ester (1 equiv) in dry THF (20 to 35 mL),lithium triethylborohydride (1 M solution in THF, 1.7 equiv) was addedslowly at 0° C. The reaction mixture was stirred at room temperature for2 h. The completion of the reaction was monitored by TLC. Reactionmixture was cooled to 0° C. and quenched using 10% ammonium chloridesolution. Solvent was removed under vacuum and resulting residue waspurified by flash column chromatography to afford the desired product.

General Procedure for Chlorination of Hetrocyclic Alcohol: Procedure B

To a stirred solution of alcohol (1 equiv) in dry DCM (10 to 20 mL),thionyl chloride (1.7 to 3 equiv) was added slowly at 0° C. The reactionmixture was warmed to rt and was refluxed for 1 h. The reaction mixturewas concentrated under vacuum and the resulting residue was diluted withDCM (20 to 50 mL). The DCM layer was washed with water (5 to 10 mL),brine solution (5 to 10 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum to give chloro compound.

General Procedure for Reductive Amination: Procedure C

To a solution of aldehyde (1 equiv) in dry THF (4 to 10 mL), amine (0.8to 1.1 equiv), acetic acid (7 equiv) was added at room temperature andstirred for 30 min. Then the reaction mixture was cooled to 0° C. andsodium triacetoxy borohydride (1.2 equiv) was added slowly. Theresulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated, the crude product was diluted with(10 to 20 mL) EtOAc and the organic layer was washed with (10-20 mL) ofbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude products were purified by flashcolumn chromatography to afford the desired product.

General Procedure for N-Alkylation: Procedure D

To a stirred solution of amine (1 mmol/0.8 to 1 equiv) in dry DMF (5 to10 mL), chloro compound (1.0 to 1.2 equiv) and potassium carbonate (2equiv) were added at rt. The resulting mixture was heated at 90° C. for16 h. It was concentrated under vacuum and the resulting residue wasdiluted with DCM (20 to 50 mL). The DCM layer was washed with water (5to 10 mL), brine solution (5 to 10 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude products were purified by flashchromatography to afford the desired product.

General Procedure for N-Alkylation: Procedure E

To a stirred solution of amine (1 mmol/1 equiv) in acetonitrile (5 to 10mL), chloro compound (1.5 to 2 equiv), triethyl amine (2 equiv) wereadded at rt. The resulting mixture was stirred at rt to 60° C. for 16 h.It was diluted with water (15 mL) and extracted with EtOAc (2×20 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The resulting crude product was purified by flashchromatography to afford the desired product.

Intermediates Synthesis Intermediate 1:5-(1-Chloroethyl)benzo[d][1,3]dioxole

Step 1: 1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-ol

To a stirred solution of 3, 4-methylenedioxy acetophenone (4.5 g, 27mmol, Alfa aesar) in dry MeOH (50 mL), NaBH₄ (1.08 g, 42 mmol, Lobachemie) was added slowly at 0° C. The reaction mixture was stirred atroom temperature for 1 h. Then the reaction mixture was concentratedunder vacuum and diluted with DCM. The DCM layer was washed with water,brine and dried over anhydrous Na₂SO₄. The solvent was removed underreduced pressure and resulting crude alcohol was used as such in thenext step. Yield: 90% (4.0 g, colorless liquid). ¹H NMR (400 MHz,CDCl₃): δ 6.89 (s, 1H), 6.89-6.75 (m, 2H), 5.95 (s, 2H), 4.81 (t, J=8.0Hz, 1H), 1.46 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0 (Hydroxyelimination mass), Rt. 2.51 min, 98.6% (Max). HPLC: (Method A) Rt. 2.499min, 99.5% (Max).

Step 2: 5-(1-Chloroethyl)benzo[d][1,3]dioxole

The title compound was synthesized by following general procedure B. Itwas used for next step without further purification. Yield: 72% (1.2 g,colorless liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.06 (d, J=4.0 Hz, 1H),6.93 (d, J=8.0 Hz. 1H), 6.86 (d, J=8.0 Hz, 1H), 6.01 (s, 2H), 2.49 (q,J=8.0 Hz, 1H), 1.74 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0(Cl-Elimination mass), Rt. 3.71 min, 80.15% (Max).

Intermediate 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazineHydrochloride

Step 1: tert-butyl4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate

The title compound was synthesized following general procedure D,starting with Intermediate 1 and N-boc piperazine. The crude product waspurified by flash chromatography, affording the title compound (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.85-6.82 (m, 2H), 6.74-6.71 (m,1H), 5.98 (m, 2H), 3.37-3.36 (m, 1H), 3.27 (br. s, 4H), 2.28-2.21 (m,4H), 1.37 (s, 9H), 1.25 (d, 3H, J=6.8 Hz). LCMS: (Method A) 335.2 (M+H),Rt. 3.10 min, 93.15% (Max). HPLC: (Method A) Rt. 3.12 min, 95.01% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine Hydrochloride

To a stirred solution of tert-butyl4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate (1.8 g,5.38 mmol) in dry dioxane (10 mL), HCl in dioxane (10 mL, 4 M,Spectrochem) was added at rt and stirred for 2 h at same temperature.The reaction mixture was concentrated under vacuum and the resultingcrude product was washed with diethyl ether to afford the title productas hydrochloride salt. Yield: 82% (1.2 g, off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 12.29 (s, 1H), 7.34 (s, 1H), 7.08 (d, 1H, J=7.7 Hz),7.00 (d, 1H, J=7.9 Hz), 6.07 (s, 2H), 4.54 (br. s, 1H), 3.81 (br. s,1H), 3.49-3.42 (m, 3H), 3.33 (br. s, 2H), 3.12 (br. s, 1H), 2.99 (br. s,1H), 1.67 (d, 3H, J=5.7 Hz). LCMS: (Method A) 235.0 (M+H), Rt. 1.65 min,98.08% (Max). HPLC: (Method A) Rt. 1.56 min, 99.86% (Max).

Intermediate 3: 6-(1-chloroethyl)-2,3-dihydrobenzo[b][1,4]dioxine

Step 1: 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-ol

The title compound was synthesized with same protocol as described forIntermediate 1, Step 1, using1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (2.0 g, 11.2 mmol)and NaBH₄ (0.49 g, 13 mmol). The resulting crude alcohol was used assuch in the next step. Yield: 99% (2.0 g, colorless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 6.80 (s, 1H), 6.79-6.76 (m, 2H), 4.59 (q, J=5.6 Hz,1H), 4.20 (s, 4H), 1.26 (d, J=5.6 Hz, 3H). LCMS: (Method B) 163.0(Hydroxy elimination mass), Rt. 2.51 min, 99.4% (Max).

Step 2: 6-(1-chloroethyl)-2,3-dihydrobenzo[b][1,4]dioxine

The title compound was synthesized according to the general procedure B.It was used in the next step without further purification. Yield: 90%(2.2 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.97 (s, 1H),6.96-6.92 (m, 1H), 6.84-6.82 (m, 1H), 5.26 (t, J=6.7 Hz, 1H), 4.23 (s,4H), 1.75 (d, J=6.7 Hz, 3H). LCMS: (Method A) 163.0 (Cl-Eliminationmass), Rt. 3.66 min, 95.3% (Max).

Intermediate 4:1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine Hydrochloride

Step 1: t-Butyl4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate

The title compound was synthesized according to the general procedure D,starting with Intermediate 3 (5 g, 25.2 mmol) and N-boc piperazine (3.96g, 21.2 mmol). The crude product was purified by flash chromatography,affording the title compound. Yield: 52% (4.6 g, brown liquid). ¹H NMR(400 MHz, DMSO-d₆): δ 6.80-6.71 (m, 3H), 4.21 (s, 5H), 3.34-3.26 (m,4H), 2.27-2.24 (m, 4H), 1.37 (s, 9H), 1.23 (d, J=6.7 Hz, 3H). LCMS:(Method A) 349.2 (M+H), Rt. 3.19 min, 80.9% (Max).

Step 2: 1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazineHydrochloride

To a stirred solution of tert-butyl4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate(4.6 g, 13.20 mmol) in dry dioxane (5.0 mL), HCl in dioxane (10.0 mL, 4M, Spectrochem) was added at 0° C. The reaction mixture was stirred atrt for 2 h. The completion of the reaction was monitored by TLC. Thereaction mixture was concentrated. Diethyl ether was added and wasevaporated again, affording the title compound. Yield: 89% (3.8 g, offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.08 (br. s, 1H), 9.48-9.18(m, 2H), 7.18 (s, 1H), 7.03 (s, 1H), 6.92 (d, J=10.6 Hz, 1H), 4.49 (s,1H), 4.24 (s, 4H), 3.41-3.15 (m, 4H), 2.91-2.71 (m, 4H), 1.64 (s, 3H).LCMS: (Method A) 249.2 (M+H), Rt. 1.64 min, 92.6% (Max).

Intermediate 7: N-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideHydrochloride

Step 1: tert-Butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-amino 5-bromo-1, 3, 4-thiadiazole (10.0 g,55.5 mmol) in dry DMF (100 mL), K₂CO₃ (15.3 g, 111.1 mmol) and 1-bocpiperazine (12.4 g, 66.65 mmol) were added at 0° C. The reaction mixturewas stirred overnight at 80° C. The reaction mixture was concentratedunder vacuum. To the resulting crude solids, DCM (200 mL) was added. TheDCM layer was washed with water (100 mL), brine (100 mL) and, dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bysilica gel column chromatography to afford the title compound. Yield:76% (12 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.51 (s, 2H),3.39 (d, J=6.9 Hz, 4H), 3.19 (d, J=7.7 Hz, 4H), 1.39 (s, 9H). LCMS:(Method A) 286.1 (M+H), Rt. 2.71 min, 97.6% (Max).

Step 2: tert-Butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g, 42.09mmol) in pyridine (120 mL), acetic anhydride (5.1 g, 50.5 mmol) wasadded at 0° C. The reaction mixture was stirred overnight at 50° C. Thereaction mixture was concentrated under vacuum and triturated withdiethyl ether (100 mL). The solid obtained was filtered, washed withdiethyl ether (20 mL), dried and taken for next step without any furtherpurification. Yield: 87% (12 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br. s, 1H), 3.45-3.34 (m, 8H), 2.11 (s, 3H), 1.42 (s,9H). LCMS: (Method A) 328.0 (M+H), Rt. 3.11 min, 86.3% (Max).

Step 3: N-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideHydrochloride

To a stirred solution of tert-butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g)in dry dioxane (100 mL), HCl in dioxane (100 mL, 4 N) was added and thereaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was suspendeddiethyl ether (50 mL). The title compound was obtained after evaporationof the solvent. Yield: 93% (9 g, white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br. s, 1H), 3.67 (s, 4H), 3.21 (s, 4H), 2.13 (s, 3H).LCMS: (Method A) 228.0 (M+H), Rt. 0.71 min, 85.3% (Max).

Intermediate 8: Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylateHydrochloride

Step 1: Ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of ethyl 2-bromothiazole-5-carboxylate (4.0 g,17.0 mmol) in dry DMF (40 mL), triethylamine (7.3 mL, 51.0 mmol,Spectrochem), followed by N-Boc piperazine (3.6 g, 19.0 mmol,GLRscientific) were added. The resulting mixture was heated at 90° C.for 12 h. It was then concentrated, diluted with DCM (200 mL), washedwith water (100 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography (3%methanol in DCM) to afford the title compound. Yield: 77% (4.5 g, whitesolid). LCMS: (Method A) 342.0 (M+H), Rt. 4.42 min, 99.5% (Max). ¹H NMR(400 MHz, CDCl₃): δ 7.88 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.57 (s, 8H),1.49 (s, 9H), 1.35 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylate Hydrochloride

To a stirred solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate (4.5 g,13.0 mmol) in dry dioxane (20 mL), HCl in dioxane (4 N, 50 mL) was addedat 0° C. and the reaction mixture was stirred at rt for 2 h. Thereaction mixture was concentrated and the resulting solid was washedwith diethyl ether and dried under vacuum. Yield: 90% (5.4 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.32 (s, 2H), 7.88 (s, 1H), 4.21(q, J=9.4 Hz, 2H), 3.96-3.73 (m, 4H), 3.55-2.41 (m, 4H), 1.24 (t, J=7.0Hz, 3H). LCMS: (Method B) 242.0 (M+H), Rt. 2.11 min, 99.8% (Max).

Intermediate 10: N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide,Hydrochloride

Step 1: Tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-chloro-5-nitro-pyrimidine (2.2 g, 13.7 mmol)in dry DMF (25 mL), triethylamine (5.7 mL, 41.3 mmol, Spectrochem)followed by N-Boc piperazine (2.8 g, 15.7 mmol) were added and theresulting mixture was heated at 90° C. for 12 h. It was concentrated andthe residue was diluted with DCM (50 mL), washed with water (15 mL) anddried over Na₂SO₄. After evaporation of the solvents, the crude productwas washed with ACN with 5% methanol to afford the title compound (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.12 (s, 2H), 3.92-3.88 (m, 4H),3.45-3.42 (m, 4H), 1.4 (s, 9H). LCMS: (Method A) 254.0 (M-(t-butyl)+H),Rt. 4.43 min, 98.03% (Max).

Step 2: Tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate (2.1 g, 6.79 mmol) inmethanol (25 mL), Pd/C (10%, 0.210 g, Aldrich) was added and thereaction mixture was stirred under H₂ atmosphere for 3 h. The reactioncompletion was monitored by TLC. The reaction mixture was filteredthrough celite and evaporated under vacuum. The crude product was usedwithout further purification. Yield: 95% (1.8 g, pale brown solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.88 (s, 2H), 4.62 (s, 2H), 3.48-3.45 (m, 4H),3.35-3.28 (m, 4H), 1.33 (s, 9H). LCMS: (Method A) 280 (M+H), Rt. 2.66min, 98.82% (Max).

Step 3: Tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 6.44 mmol) indry DCM (18 mL), pyridine (0.7 mL, 9.67 mmol, spectrochem), aceticanhydride (0.9 mL, 9.67 mmol, spectrochem) and dimethyl aminopyridine(0.036 g, 2%, spectrochem) were added. The resulting mixture was stirredat rt for 12 h. The reaction mixture was concentrated under reducedpressure and the resulting solid was suspended in HCl (1.5 N in water,15 mL). The solid was filtered and washed with water (200 mL) to affordthe title compound. Yield: 87% (1.8 g, off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 9.85 (s, 1H), 8.51 (s, 2H), 3.66-3.61 (m, 4H),3.33-3.31 (m, 4H), 2.00 (s, 3H), 1.41 (s, 9H). LCMS: (Method A) 322(M+H), Rt. 3.1 min, 98.4% (Max).

Step 4: N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of tert-butyl4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 5.6 mmol)in dry dioxane (5 mL) at 0° C., a solution of HCl in dioxane (4 N, 15mL) was added and the reaction mixture was stirred 3 h at rt. It wasconcentrated and the resulting product washed with diethyl ether,affording the title compound. Yield: 83% (1.8 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 10.9 (s, 1H), 9.92 (s, 1H), 8.86 (s, 2H),3.22-3.17 (m, 4H), 3.02-2.78 (m, 4H), 2.06 (s, 3H). LCMS: (Method B)222.0 (M+H), Rt. 2.36 min, 95.34% (Max)

Intermediate 16: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazineHydrochloride

Step 1:(R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (105.7 g, 644.6mmol), (R)-(+)-2-methyl-2-propanesulfinamide (85.79 g, 709 mmol) in THF(1.0 L), titanium(IV) ethoxide (294.06 g, 1289.2 mmol) was added at rtover 30 min and refluxed for 35 h. The reaction was monitored by HPLC.The reaction mixture was cooled to rt and slowly quenched with water(500 mL). The precipitate observed was filtered through celite bed (100g) and washed with EtOAc (2.0 L). The organic layer was washed withwater (500 mL), brine solution (300 mL) and dried over Na₂SO₄ (100 g)and evaporated under vacuum at 50° C. The resulting crude product wascodistilled with toluene (2×500 mL) and used as such for next stepwithout any further purification (164 g, brown liquid).

LCMS: (Method A) 268.0 (M+H), Rt. 3.87 min, 83.05% (Max).

HPLC: (Method A) Rt. 3.81 min, 57.62% (Max).

Step 2:(R)—N—((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

To a stirred solution of(R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(96 g, 359 mmol) in THF (960 mL), L-Selectride (539 mL, 539 mmol, 1 Msolution in THF) was added under nitrogen atmosphere at −50° C. over 30min and stirred for 1 h. The completion of the reaction was confirmed byTLC. The reaction mixture was quenched with methanol (150 mL), water(750 mL) and stirred overnight at rt. The aqueous layer was extractedwith EtOAc (2×300 mL). The combined organic layer was washed with sat.NH₄Cl (2×250 mL), brine (250 mL), dried over Na₂SO₄ and evaporated undervacuum at 50° C. The resulting crude product (as light brown thick oil)was diluted with pet ether (250 mL) and stirred at −20° C. for 30 min.The resulting precipitate was filtered and washed with pet ether (2×100mL). It was dried under vacuum to give the title compound. Yield: 70.2%(68 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H),6.83-6.77 (m, 2H), 5.99-5.95 (m, 2H), 5.25 (d, J=5.2 Hz, 1H), 4.30 (q,J=6.0 Hz, 1H), 1.39 (d, J=1.6 Hz, 3H), 1.11-1.06 (m, 9H). LCMS: (MethodA) 270.0 (M+H), Rt. 3.66 min, 99.65% (Max). HPLC: (Method A) Rt. 3.62min, 99.69% (Max). Chiral HPLC: (Method C) Rt. 9.71 min, 100%.

Step 3: (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

To a stirred solution of(R_(S))—N—((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide(68 g, 252 mmol) in MeOH (680 mL), thionyl chloride (74.3 g, 630 mmol)was added at 0° C. over 15 min and the resulting mixture was stirred atrt for 1 h. The completion of the reaction was confirmed by TLC. Thereaction mixture was concentrated under vacuum at 50° C. The resultingresidue was suspended in EtOAc (300 mL), filtered and washed with EtOAc(150 mL). The product was basified with 30% aqueous ammonia solution(300 mL) and extracted with EtOAc (2×250 mL). The combined organic layerwas washed with brine solution (1×150 mL) and dried over Na₂SO₄. Thesolvent was evaporated at under vacuum to give the title compound.Yield: 92.84% (38.3 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.95(s, 1H), 6.81-6.77 (m, 2H), 5.95 (s, 2H), 3.90 (q, J=6.56 Hz, 1H), 1.85(s, 2H), 1.19 (m, J=6.56 Hz, 3H). LCMS: (Method A) 149.0 (M−16), Rt.1.65 min, 99.56% (Max). HPLC: (Method A) Rt. 1.60 min, 99.61% (Max).Chiral HPLC: (Method B) Rt 11.11 min, 100%.

Step 4: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

To a stirred solution of (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine(41 g, 248 mmol) in DIPEA (86.6 mL, 496 mmol),N,N-bis(2-chloroethyl)-p-toluene sulfonamide (80.74 g, 273 mmol) wasadded at rt and the resulting mixture was heated at 105° C. overnight.The completion of the reaction was confirmed by TLC and the reactionmixture was diluted with water (1000 mL) and extracted with EtOAc (2×500mL). The combined organic layer was washed with water (200 mL), brinesolution (200 mL) and dried over Na₂SO₄. After evaporation of thesolvent, the resulting crude solid was suspended in pet ether (350 mL)and stirred for 10 min at rt. The suspension was filtered and was washedwith Et₂O (2×200 mL) and dried under vacuum to give the title compound.

Yield: 63.2% (61 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.59(d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.81-6.77 (m, 1H), 6.69 (d,J=7.4 Hz, 1H), 5.96 (s, 2H), 3.32 (q, J=7.76 Hz, 1H), 2.81-2.80 (m, 4H),2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 389.2 (M+H), Rt. 3.40 min, 98.09% (Max). HPLC: (Method A) Rt. 3.30min, 98.69% (Max). Chiral HPLC: (Method D) Rt. 15.79 min, 100.00%

Step 5: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazineHydrochloride

To a mixture of(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (61 g, 157mmol) and 4-hydroxy benzoic acid (65.01 g, 471 mmol), HBr in acetic acid(244 mL) was added at 0° C. and the reaction mixture was stirred at rtovernight. The completion of the reaction was confirmed by TLC. Thereaction mixture was diluted with water (400 mL). The precipitate wasfiltered through celite bed and washed with water (200 mL). The aqueousfilterate was washed with EtOAc (4×300 mL) and basified up to pH 11 withNaOH pellet (30 g) at 0° C. (during basification the colour of aqueouswas converted to light back). The product was extracted with EtOAc(4×300 mL). The combined organic layer was dried over Na₂SO₄ andevaporated under vacuum. The resulting light black oil was diluted in1,4 Dioxane (50 mL) and cooled to 0° C. and 4.5 N HCl solution indioxane (100 mL) was added and stirred for 15 min at rt. The solvent wasevaporated at 45° C. under reduced pressure to get the title compound(pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 7.32 (s,1H), 7.06-6.99 (m, 2H), 6.07 (s, 2H), 4.55-4.52 (m, 1H), 3.80-3.61 (m,2H), 3.05-2.95 (m, 2H), 2.51-2.50 (m 4H), 1.68 (s, 3H). LCMS: (Method A)235.3 (M+H), Rt. 1.53 min, 95.85% (Max). HPLC: (Method A) Rt. 1.52 min,95.06% (Max). Chiral HPLC: (Method A) Rt. 8.11 min, 100%.

Intermediate 21: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

Step 1: 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 6-bromo-2,3-dihydro-1-benzofuran (1 g,5.03 mmol) as starting material. The crude product was purified by flashchromatography to give the title compound. Yield: 73.7% (0.6 g, paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (d, J=7.64 Hz, 1H),7.37-7.35 (d, J=7.68 Hz, 1H), 7.26 (s, 1H), 4.58 (t, J=8.76 Hz, 2H),3.24 (t, J=8.76 Hz, 2H), 2.53 (s, 3H). LCMS: (Method A) 163.2 (M+H), Rt.3.01 min, 97.60% (Max).

Step 2: 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol

The title compound was prepared according to the procedure described forIntermediate 17, Step 2, using 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one(0.6 g, 3.7 mmol) as starting material. After evaporation of thesolvent, the title compound was isolated and used without furtherpurification. Yield: 88.30% (0.53 g, colourless liquid). ¹H NMR (400MHz, DMSO-d₆): δ 7.11 (d, J=7.6 Hz, 1H), 6.77-6.75 (m, 1H), 6.71 (s,1H), 5.04 (d, J=4.4 Hz, 1H), 4.63-4.61 (m, 1H), 4.48 (t, J=8.8 Hz, 2H),3.11 (t, J=8.8 Hz, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 147.0(M−17H), Rt. 2.64 min, 89.95% (Max).

Step 3: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

The title compound was synthesized from1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol (0.53 g, 3.23 mmol), accordingto the general procedure B. The crude product was used in the next stepwithout further purification. Yield: quantitative (0.58 g, brown oil).¹H NMR (400 MHz, DMSO-d₆): δ 7.20 (d, J=7.56 Hz, 1H), 6.93-6.91 (m, 1H),6.87 (s, 1H), 5.29-5.24 (m, 1H), 4.53 (t, J=8.72 Hz, 2H), 3.15 (t,J=8.76 Hz, 2H), 1.75 (d, J=6.76 Hz, 3H). LCMS: (Method A) 147.0 (M−35H),Rt. 3.76 min, 83.62% (Max).

Intermediate 25:2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-oneDihydrochloride

Step 1: tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate

To a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (1g, 4.69 mmol) in dry CCl₄ (10 mL), N-bromosuccinimide (0.83 g, 4.69mmol) was added at 10° C. The reaction mixture was stirred at 10-15° C.for 2 h. It was then evaporated under reduced pressure. Water (10 mL)was added and the desired product was extracted with EtOAc (2×30 mL).The combined organic layer was dried over Na₂SO₄ and concentrated. Theresulting crude product was purified by flash column chromatography,affording the title product. Yield: 99% (1.4 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 5.50 (s, 1H), 3.74-3.71 (m, 2H), 2.69-2.66 (m,2H), 1.46 (s, 9H). LCMS: (Method A) 193.8 (M-Boc+H), Rt. 2.93 min,81.51% (Max).

Step 2:tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.31 g, 5.36 mmol) in isopropanol (15 mL), tert-butyl3-bromo-2,4-dioxopiperidine-1-carboxylate obtained in the first step(1.3 g, 4.46 mmol) was added at rt. The reaction mixture was stirredovernight at 90° C. It was cooled down to rt and evaporated underreduced pressure. Water (10 mL) was added and the desired product wasextracted with diethyl ether (2×30 mL), dried over Na₂SO₄ andconcentrated, affording the title product. Yield: 74% (1.42 g, yellowsolid). LCMS: (Method A) 239.0 (M-Boc+H), Rt. 0.70 min, 48.39% (Max).

Step 3: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-oneDihydrochloride

To a stirred solution oftert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylateobtained in previous step (1.3 g, 2.96 mmol) in 1,4-dioxane (10 mL), HClin dioxane (4 M solution, 13 mL, 10V) was added at 0° C. The reactionmixture was stirred for 2 h at rt. It was evaporated and DCM (15 mL) wasadded and evaporated. This procedure was repeated twice, affording thetitle product which was used without any further purification. Yield:99% (0.82 g, off white solid).

Intermediate 29: 1-(3-(Trifluoromethyl)pyridin-2-yl)piperazine

To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (1 g, 5.50mmol) in n-Butanol (10 mL), 1-piperazine (6.63 g, 77.12 mmol) was addedand the reaction mixture was stirred at 100° C. for 24 h. The reactioncompletion was confirmed by TLC. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultingmixture was diluted with ethyl acetate (30 mL) and neutralized withsaturated sodium bicarbonate solution (4 mL), and extracted with EtOAc(2×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude was purified bycolumn chromatography to afford the title compound. Yield: 63% (0.8 g,colorless gum). ¹HNMR (400 MHz, DMSO-d₆): δ 8.50 (d, J=3.6 Hz, 1H), 8.03(dd, J=7.8, 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 3.11-3.08 (m, 4H), 2.81-2.79(m, 4H). LCMS: (Method F) 232.0 (M+H), Rt. 2.10 min, 96.01% (Max).

Intermediate 30: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine,Hydrochloride

Step 1: tert-butyl4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of N-boc piperazine (5.5 g, 29.5 mmol), TEA (11.9g, 11.8 mmol) in DMF (55 mL), Intermediate 21 (7.5 g, 41.3 mmol) wasadded at RT and the resulting mixture was heated at 70° C. overnight.Completion of the reaction was monitored by TLC. The reaction mixturewas concentrated under reduced pressure and the resulting crude mixturewas dissolved in EtOAc (100 mL). The organic layer was washed with water(50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by flash chromatography (12% EtOAc in pet ether aseluent) to give the title compound. Yield: 52% (58% purity) (5.1 g,brown gum). ¹H NMR (400 MHz, CDCl₃): δ 7.19-7.12 (m, 1H), 6.88-6.77 (m,2H), 4.62-4.59 (m, 2H), 3.42-3.39 (m, 4H), 3.36-3.31 (m, 1H), 3.23-3.18(m, 2H), 2.44-2.34 (m, 4H), 1.46 (s, 9H), 1.35 (d, J=6.4 Hz, 3H). LCMS:(Method A) 333.3 (M+H), Rt. 3.12 min, 58.09% (Max).

Step 2: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine, Hydrochloride

To a stirred solution of tert-butyl4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate (5.1 g,15.3 mmol) in 1,4 dioxane (25 mL), HCl solution in dioxane (4 M, 25 mL)was added at 0° C. The resulting mixture was stirred at rt for 2 h.Completion of the reaction was monitored by TLC. The reaction mixturewas evaporated at 40° C. under reduced pressure. The resulting productwas triturated with n-hexanes (2×100 mL) and decanted two times. It wasthen dried at 40° C. under reduced pressure to give the title compound.Yield: 66.2% (3.1 g, Off white solid). ¹H NMR (400 MHz, DMSO-d6): δ 7.15(d, J=7.2 Hz, 1H), 6.76-6.71 (m, 2H), 4.36-4.30 (m, 2H), 3.55-3.53 (m,4H), 3.43-3.41 (m, 1H), 3.15-3.11 (m, 2H), 2.53-2.43 (m, 4H), 1.31-1.29(m, 3H). LCMS: (Method A) 233.2 (M+H), Rt. 1.67 min, 90.31% (Max).

Example 5:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

Step 1: tert-butyl 4-carbamothioylpiperazine-1-carboxylate

To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at roomtemperature and stirred for 2 h. The reaction mixture was heated at 50°C. for 1 h. It was cooled down to 0° C. and methanolic ammonia solution(50 mL, 7 N) was added. The mixture was stirred at 60° C. for 20 h. Itwas then diluted with water and extracted with EtOAc. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified by flash chromatography to give the title compound.Yield: 92% (4.0 g, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.2 (m,2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (MethodA) 246.2 (M+H), Rt. 2.93 min, 95.3% (Max).

Step 2: tert-Butyl 4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (0.5 g, 2.08 mmol) in dioxane(10 mL), triethyl amine (0.22 mL, 2.6 mmol) and2-bromo-1-phenylethan-1-one (0.52 g, 2.6 mmol) were added at rt. Theresulting mixture was stirred at 90° C. for 20 h. The completion of thereaction was monitored by TLC. It was diluted with water and extractedwith EtOAc. The organic layer was separated, dried over anhydrousNa₂SO₄, concentrated under vacuum. The resulting crude product was takenas such for the next step. Yield: 86% (0.5 g, colorless liquid).

Step 3: 4-Phenyl-2-(piperazin-1-yl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate (0.5 g) in dry dioxane(2 mL), HCl in dioxane (10 mL, 4 N) was added at room temperature andstirred for 3 h at same temperature. The reaction mixture wasconcentrated under reduced pressure and the resulting crude product wassuspended in diethyl ether (10 mL). It was filtered and dried undervacuum to afford the title compound. Yield: 75% (350 mg, yellow solid).LCMS: (Method A) 246.2 (M+H), Rt. 2.85 min, 71.5% (Max).

Step 4:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

The title compound was synthesized by following general procedure E,using 4-phenyl-2-(piperazin-1-yl)thiazole hydrochloride (0.2 g, 0.8mmol) and Intermediate 1 (0.3 g, 1.6 mmol). The reaction mixture wasstirred at rt for 16 h. The crude product was purified by flashchromatography, affording the title compound (yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.84-7.82 (m, 2H), 7.40-7.36 (m, 3H), 7.30-7.26 (m,1H), 7.14-6.99 (m, 3H), 6.06 (s, 2H), 4.61-4.48 (m, 1H), 4.18-3.98 (m,2H), 3.43-3.33 (m, 2H) 3.12-2.98 (m, 2H), 2.59-2.49 (m, 2H), 1.63 (br.s,3H). LCMS: (Method A) 394.0 (M+H), Rt. 3.87 min, 98.3% (Max). HPLC:(Method A) Rt. 3.89 min, 99.3% (Max).

Example 6:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

Step 1: tert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.0 g, 4.0 mmol) in dioxane (20 mL), triethyl amine(0.6 mL, 8.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.2 g,5.3 mmol) was added at rt and stirred at 90° C. for 20 h. The completionof the reaction was monitored by TLC. The reaction mixture was dilutedwith water (10 mL) and extracted with EtOAc (2×25 mL). The organic layerwas separated, dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the resulting crude product was taken as such for the nextstep. Yield: 53% (0.8 g, pale yellow liquid).

Step 2: 4-(4-Methoxyphenyl)-2-(piperazin-1-yl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate (0.8 g) indry dioxane (5 mL), HCl in dioxane (4 M, 10 mL) was added at rt andstirred for 3 h. The reaction mixture was concentrated under vacuum. Theresulting crude product was triturated in diethyl ether (10 mL),filtrated and dried under vacuum to afford the title compound. Yield:68% (400 mg, yellow solid). LCMS: (Method A) 276.0 (M+H), Rt. 2.82 min,69.9% (Max).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

The title compound was synthesized by following general procedure E,using 4-(4-methoxyphenyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.5g, 2.7 mmol) and Intermediate 1 (0.9 g, 5.4 mmol). The reaction mixturewas stirred at rt for 16 h. The crude product was purified by flashchromatography, affording the title compound (pale yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.76 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 6.94-6.91(m, 3H), 6.86-6.84 (m, 1H), 6.78-6.76 (m, 1H), 5.99 (m, 2H), 3.76 (s,3H), 3.43-3.42 (m, 5H), 2.50 (m, 2H) 2.42-2.41 (m, 2H), 1.30 (d, J=6.8Hz, 3H). LCMS: (Method A) 424.0 (M+H), Rt. 3.86 min, 98.7% (Max). HPLC:(Method A) Rt. 3.85 min, 99.3% (Max).

Example 7:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMSO(5 mL), K₂CO₃ (0.15 g, 11.11 mmol) and 2-bromo thiazole (0.066 g, 0.407mmol) were added. The reaction mixture was heated in a microwave at 150°C. for 3 h. The reaction mixture was cooled and concentrated undervacuum. The resulting crude product was purified by MD Autoprep (MethodB) to afford the title compound (off white solid). ¹H NMR (400 MHz,CDCl₃): δ 7.20 (d, J=4.0 Hz, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 6.57 (s,1H), 5.97 (s, 2H), 3.48 (s, 4H), 3.36 (s, 1H), 2.60-2.53 (m, 4H), 1.37(s, 3H). LCMS: (Method A) 318.0 (M+H), Rt. 2.04 min, 94.4% (Max). HPLC:(Method A) Rt. 2.04 min, 98.6% (Max).

Example 9:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylpyrimidine

To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMF (5mL), DIPEA (0.22 g, 1.7 mmol) and 2-chloro-4-methyl pyrimidine (0.109 g,0.8 mmol) were added at rt and the reaction mixture was stirred at 120°C. for 12 h. It was cooled down to rt and concentrated under vacuum. Theresulting crude product was purified by flash chromatography to affordthe title compound (brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (d,J=4.8 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 1H),6.48 (d, J=4.8 Hz, 1H), 5.99 (m, 2H), 3.70-3.66 (m, 4H), 3.40-3.34 (m,1H), 2.43-2.39 (m, 2H), 2.34-2.31 (m, 2H) 2.24 (s, 3H), 1.28 (d, J=6.4Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.57 min, 98.1% (Max). HPLC:(Method A) Rt. 2.59 min, 98.6% (Max).

Example 10:1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(pyridin-2-yl)piperazine

The title compound was synthesized by following general procedure D,using 1-pyridyl-2-piperazine (0.2 g, 1.3 mmol) and Intermediate 1 (0.3g, 1.63 mmol). The resulting crude product was purified by silica gelcolumn, affording the title compound (colorless oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.07 (dd, J=2.0, 4.8 Hz, 1H), 7.51-7.46 (m, 1H), 6.88 (s,1H), 6.84-6.82 (m, 1H), 6.76-6.74 (m, 2H), 6.61-6.58 (m, 1H), 5.98 (m,2H), 3.43-3.40 (m, 4H), 3.34-3.33 (m, 1H), 2.47-2.44 (m, 2H), 2.39-2.35(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 312.0 (M+H), Rt. 1.83min, 98.0% (Max). HPLC: (Method A) Rt. 1.82 min, 98.4% (Max).

Example 11:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

The title compound was synthesized by following general procedure D,using 2-(piperazin-1-yl)pyrimidine (0.2 g, 1.21 mmol) and Intermediate 1(0.366 g, 1.82 mmol). The resulting crude product was purified by MDAutoprep (Method B), affording the title compound (colourless oil). ¹HNMR (400 MHz, MeOH-d₄): δ 8.36 (d, J=4.8 Hz, 2H), 6.96 (s, 1H),6.90-6.84 (m, 2H), 6.66 (t, J=4.8 Hz, 1H), 5.99 (s, 2H), 3.92-3.90 (m,4H), 3.33 (m, 1H), 2.83 (m, 4H), 1.59 (d, J=6.0 Hz, 3H). LCMS: (MethodA) 313.2 (M+H), Rt. 2.45 min, 99.4% (Max). HPLC: (Method A) Rt. 2.44min, 99.8% (Max).

Example 12:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

Step 1: t-Butyl 4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.2 g, 4.01 mmol) in THF (10 mL), triethyl amine (0.5mL, 5.3 mmol) and 1-bromo-3-methylbutan-2-one (1.0 mL, 5.3 mmol) wereadded at rt. The resulting mixture was stirred for 16 h at 90° C. Thecompletion of the reaction was monitored by TLC. The reaction mixturewas quenched with water and extracted with EtOAc. The organic layer wasdried over anhydrous Na₂SO₄, concentrated under vacuum and the resultingcrude product was taken as such for next step. Yield: 80% (0.8 g, paleyellow oil). LCMS: (Method A) 312.0 (M+H), Rt. 3.24 min, 95.2% (Max).

Step 2: 4-Isopropyl-2-(piperazin-1-yl)thiazole hydrochloride

To a stirred solution of tert-butyl4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate (0.8 g, 2.4 mmol) indry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt andstirred for 2 h at same temperature. The reaction mixture wasconcentrated under vacuum and the crude product was washed with diethylether to afford the title compound. Yield: 93% (1.2 g, pale yellow oil).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

The title compound was synthesized by following general procedure D,using 4-isopropyl-2-(piperazin-1-yl)thiazole hydrochloride (0.57 g, 2.3mmol) and Intermediate 1 (0.5 g, 2.3 mmol). The resulting crude productwas purified by MD Autoprep (Method C), affording the title compound(pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.98 (m, 2H),3.41-3.11 (m, 5H), 2.74-2.72 (m, 1H), 2.46-2.38 (m, 4H), 1.27 (d, J=6.8Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). LCMS: (Method A) 360.0 (M+H), Rt. 2.71min, 94.5% (Max). HPLC: (Method A) Rt. 2.69 min, 98.8% (Max).

Example 13:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

Step 1: tert-Butyl4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 2 g, 13.75 mmol) in dioxane (20 mL), triethyl amine(1.7 mL, 12.24 mmol) and 1-bromo-3,3,3-trifluoro acetone (3.2 g, 16.5mmol) were added and stirred at 90° C. for 3 h. The completion of thereaction was monitored by TLC. The reaction mixture was quenched withwater (10 mL) and extracted with ethyl acetate (2×25 mL). The organiclayer was separated, dried over anhydrous Na₂SO₄, concentrated undervacuum and was used as such for next step. Yield: 75% (1.0 g, whitesolid). ¹H NMR (300 MHz, DMSO-d₆): δ 7.57 (s, 1H), 3.42 (m, 8H), 1.40(s, 9H). LCMS: (Method A) 338.0 (M+H), Rt. 5.37 min, 99.0% (Max).

Step 2: 2-(Piperazin-1-yl)-4-(trifluoromethyl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (1.0 g, 2.93mmol) in dry dioxane, HCl in dioxane (4 N, 15 mL) was added and thereaction mixture was stirred at rt for 1 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was trituratedin diethyl ether, filtrated and dried under vacuum to afford the titlecompound. Yield: 99% (700 mg, white solid). ¹H NMR (400 MHz, DMSO-d₆): δ9.22 (br. s, 2H), 7.66 (s, 1H), 3.68-3.64 (m, 4H), 3.21 (m, 4H). LCMS:(Method A) 238.0 (M+H), Rt. 2.33 min, 99.7% (Max).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

To a stirred solution of 2-(piperazin-1-yl)-4-(trifluoromethyl)thiazolehydrochloride (0.26 g, 1.07 mmol) in dry DMF (3 mL), Intermediate 1(0.19 g, 1.07 mmol) and triethyl amine (0.272 g, 2.69 mmol) were addedand the reaction mixture was stirred at 80° C. for 16 h. The reactionmixture was concentrated, the crude product was diluted with ethylacetate (10 mL) and the organic layer was washed with brine (10 mL). Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated to afford the title compound (colorless oil). ¹H NMR (400MHz, DMSO-d₆): δ 6.96 (s, 1H), 6.88 (s, 1H), 6.76-7.75 (m, 2H), 5.91 (s,2H), 3.55-3.45 (m, 4H), 3.38 (q, J=6.4 Hz, 1H), 2.62-2.49 (m, 4H),2.56-2.51 (m, 4H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (Method A) 386.0 (M+H),Rt. 3.55 min, 97.4% (Max). HPLC: (Method A) Rt. 3.54 min, 98.7% (Max).

Example 14:1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-methylpyridin-2-yl)piperazine

The title compound was synthesized according the general procedure D,using Intermediate 2 and 2-fluoro-5-methyl pyridine. The crude productwas purified by flash chromatography to afford the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (s, 1H), 7.36-7.33 (m,1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.70(d, J=8.4 Hz, 1H), 5.99 (m, 2H), 3.37-3.35 (m, 5H), 2.47-2.44 (m, 2H),2.38-2.36 (m, 2H), 2.12 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 326.2 (M+H), Rt. 1.96 min, 97.6% (Max). HPLC: (Method A) Rt. 1.96min, 98.1% (Max).

Example 15:(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazoleor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

The two enantiomers of Example A were separated by chiral preparativeHPLC (Method PE). The first eluting compound has Rt. 5.76 min (Method C)(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99-5.98 (m, 2H),3.40-3.36 (m, 1H), 3.32-3.29 (m, 4H), 2.47-2.44 (m, 2H), 2.41-2.37 (m,2H), 2.11 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 332.0 (M+H),Rt. 2.06 min, 96.3% (Max). HPLC: (Method A) Rt 2.05 min, 99.5% (Max),99.4% (254 nm). HPLC chiral purity: (Method C) Rt. 5.76 min, 100% (Max).Example 15 is the second eluting compound with Rt. 7.44 min (Method C)(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99 (s, 2H),3.42-3.37 (m, 1H), 3.32-3.30 (m, 4H), 2.47-2.44 (m, 2H), 2.40-2.36 (m,2H), 2.11 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 332.0 (M+H),Rt. 2.04 min, 99.2% (Max). HPLC: (Method A) Rt. 2.05 min, 99.2% (Max).HPLC chiral purity: (Method C) Rt. 7.44 min, 99.83% (Max).

Example 16:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

Step 1: tert-butyl4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.3 g, 5.3 mmol) in dioxane (10 mL), TEA (1 mL, 7mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.94 mL, 6.8 mmol) were addedat rt and stirred for 16 h at 90° C. The completion of the reaction wasmonitored by TLC. The reaction mixture was quenched with water andextracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄,concentrated under vacuum and the resulting crude product was taken assuch for next step without further purification. Yield: 88% (1.5 g,black liquid). LCMS: (Method A) 326.2 (M+H), Rt. 3.75 min, 60.4% (Max).

Step 2: 4-(tert-Butyl)-2-(piperazin-1-yl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate (1.5 g, 4.61mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added andthe reaction mixture was stirred at rt for 2 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was trituratedin diethyl ether (100 mL), filtered and dried under vacuum to afford thetitle compound. Yield: 63% (1.02 g, black solid).

Step 3:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

The title compound was synthesized following the general procedure D,using 4-(tert-butyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.732 g,2.8 mmol) and Intermediate 1 (0.28 g, 2.8 mmol) and the crude productwas purified by flash chromatography (pale yellow oil). ¹H NMR (400 MHz,DMSO-d₆): δ 6.89 (s, 1H), 6.85 (d, J=7.6 Hz), 6.76 (d, J=7.6 Hz, 1H),6.33 (s, 1H), 5.99 (m, 2H), 3.40 (m, 1H), 3.37-3.30 (m, 4H), 2.49-2.46(m, 2H), 2.43-2.40 (m, 2H), 1.28 (d, J=6.8 Hz, 3H), 1.19 (s, 9H). LCMS:(Method A) 374.0 (M+H), Rt. 3.40 min, 98.6% (Max). HPLC: (Method A) Rt.3.39 min, 99.7% (Max).

Example 17: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

Step 1: Ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 3.0 g, 12 mmol) in dioxane (10 mL), TEA (2.6 mL, 16mmol) and 3-bromo-ethyl pyruvate (2.1 mL, 16 mmol) were added at rt andthe mixture was stirred at 90° C. for 16 h. The completion of thereaction was monitored by TLC. The reaction mixture was quenched withwater and extracted with EtOAc. The organic layer was dried overanhydrous Na₂SO₄, concentrated under vacuum and the resulting crudeproduct was taken as such for next step. Yield: 95% (4 g, black solid).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate Hydrochloride

To a stirred solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate (4.0 g,11.73 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was addedat rt and stirred for 2 h. The reaction mixture was concentrated undervacuum and the resulting crude product was triturated in diethyl ether(25 mL), filtered and dried under vacuum to afford the title compound.Yield: 90% (3.2 g, black solid). LCMS: (Method A) 242.0 (M+H), Rt. 1.88min, 90.7% (Max).

Step 3: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

The title compound was synthesized following the general procedure D,using ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride andIntermediate 1 and the crude product was purified by flashchromatography followed by MD Autoprep (Method B) (yellow solid). ¹HNMR(400 MHz, DMSO-d₆): δ 7.66 (d, J=2.0 Hz, 1H), 6.88 (s, 1H), 6.84 (d,J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 4.21-4.20 (m, 2H),3.38-3.32 (m, 5H), 2.49-2.40 (m, 4H), 1.26-1.23 (m, 6H). LCMS: (MethodA) 390.0 (M+H), Rt. 2.99 min, 97.8% (Max). HPLC: (Method A) Rt. 2.95min, 98.9% (Max).

Example 18:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicAcid

To a stirred solution of Example 17 (0.2 g) in dry THF (10 mL), 5% NaOHin water (5 mL) was added slowly at rt and the mixture was stirred for16 h at same temperature. It was then concentrated under vacuum,neutralised to pH=6 with 2N HCl and extracted with DCM (20 mL). Theorganic layer was washed with brine (10 mL), water (10 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography followed by MD Autoprep(Method B) to afford the title compound (off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.88 (d, J=8.0 Hz, 1H).6.76 (d, J=8.0 Hz, 1H), 6.00-5.99 (m, 2H), 3.35-3.36 (m, 5H), 2.51-2.49(m, 2H), 2.44-2.40 (m, 2H), 1.29-1.27 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 362.0 (M+H), Rt. 2.29 min, 95.5% (Max). HPLC: (Method A) Rt. 2.30min, 95.9% (Max).

Example 19:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

Step 1: t-Butyl 4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 2.0 g, 8.16 mmol) in dioxane (20 mL), TEA (1.7 mL,10.6 mmol) and 1-bromobutan-2-one (1.2 mL, 10 mmol) were added andstirred at 80° C. for 16 h. The completion of the reaction was monitoredby TLC. The reaction mixture was quenched with water (10 mL) andextracted with EtOAc (2×25 mL). The organic layer was separated, driedover anhydrous Na₂SO₄, concentrated under vacuum. The resulting productwas taken as such for next step. Yield: 86% (2.1 g, pale yellow solid).LCMS: (Method A) 298.0 (M+H), Rt. 2.94 min, 93.1% (Max).

Step 2: 4-Ethyl-2-(piperazin-1-yl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate (1.9 g, 6.3 mmol) in drydioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added and the reactionmixture was stirred at rt for 2 h. The reaction mixture was concentratedunder vacuum and the crude product was triturated in diethyl ether (15mL), filtered and dried under vacuum to afford the title compound.Yield: 53% (0.8 g, black solid).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

The title compound was synthesized following the general procedure D,using 4-ethyl-2-(piperazin-1-yl)thiazole hydrochloride (1.1 g, 4.7 mmol)and Intermediate 1 (0.9 g, 4.7 mmol). The crude product was purified byflash chromatography (pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H),6.35 (s, 1H), 5.98 (m, 2H), 3.40-3.37 (m, 1H), 3.37-3.30 (m, 4H),2.51-2.38 (m, 6H), 1.28 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). LCMS:(Method A) 346.0 (M+H), Rt. 2.31 min, 98.0% (Max). HPLC: (Method A) Rt.2.34 min, 99.4% (Max).

Example 20:1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-chloropyridin-3-yl)piperazine

The title compound was synthesized following the general procedure D,using Intermediate 1 and 1-(5-chloro-2-pyridyl) piperazine. The crudeproduct was purified by flash chromatography (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.07 (d, J=2.4 Hz, 1H), 7.57-7.54 (m, 1H),6.88-6.74 (m, 4H), 5.98 (m, 2H), 3.42 (q, J=6.4 Hz, 1H), 2.46-2.43 (m,2H), 2.37-2.34 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 346.0(M+H), Rt. 3.27 min, 98.7% (Max). HPLC: (Method A) Rt 3.25 min, 99.2%(Max).

Example 21:1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-methylpyridin-2-yl)piperazine

To a stirred solution of Intermediate 2 (0.12 g, 0.5 mmol) in dry DMF (2mL), 2-fluoro-6-methyl pyridine (0.11 g, 0.99 mmol) and DIPEA (0.26 g,2.4 mmol) were added at rt and the reaction mixture was stirred at 120°C. for 16 h. The reaction mixture was cooled to rt and concentratedunder vacuum. The resulting crude product was purified by flashchromatography followed by preparative HPLC (Method PA) to afford thetitle compound (brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.40-7.36(m, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H),6.55-6.46 (m, 2H), 5.98 (s, 2H), 3.410-3.415 (m, 5H), 2.38-2.37 (m, 4H),2.28-2.30 (m, 3H), 1.29 (d, J=7.2 Hz, 3H). LCMS: (Method A) 326.2 (M+H),Rt. 1.89 min, 94.9% (Max). HPLC: (Method A) Rt 1.91 min, 96.6% (Max).

Example 22:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-amine

The title compound was synthesized by following procedure D, usingIntermediate 2 (0.228 g, 0.85 mmol) and 4-amino-2-chloro pyrimidine (0.1g, 0.77 mmol). The crude product was purified by flash chromatographyfollowed by MD Autoprep (Method B) (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.70 (d, J=5.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.36 (s, 2H), 5.98 (m, 2H), 5.69 (d, J=5.6Hz, 1H), 3.6-3.58 (m, 4H), 3.33-3.32 (m, 1H), 2.38-2.34 (m, 2H),2.31-2.27 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 328.0 (M+H),Rt. 1.85 min, 97.2% (Max). HPLC: (Method A) Rt. 1.84 min, 97.1% (Max).

Example 23:N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

Step 1: N-(2-Chloropyrimidin-4-yl)acetamide

To a stirred solution of 4-amino-2-chloro pyrimidine (0.6 g, 4.65 mmol)in DCM (5 mL), pyridine (1.8 mL) and acetic anhydride (0.71 g, 6.9 mmol)were added at 0° C. and stirred at 75° C. for 6 h. The reaction mixturewas concentrated under vacuum and the resulting crude product wasdissolved in EtOAc (15 mL). The organic layer was washed with water (10mL), brine (10 mL) and dried over anhydrous Na₂SO₄. After concentrationunder vacuum, the crude product was taken as such for next step. Yield:56.9% (0.45 g, pale brown solid). LCMS: (Method A) 172.0 (M+H), Rt. 1.58min, 80.2% (Max).

Step 2:N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

The title compound was synthesized following procedure D and usingIntermediate 2 (0.25 g, 0.93 mmol) andN-(2-chloropyrimidin-4-yl)acetamide (0.19 g, 1.12 mmol). The crudeproduct was purified by flash chromatography followed by MD Autoprep(Method B) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (s, 1H),8.18 (d, J=5.6 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H),6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=1.6, 8 Hz, 1H), 5.98 (m, 2H),3.68-3.66 (m, 4H), 3.37-3.36 (m, 1H), 2.42-2.38 (m, 2H), 2.35-2.31 (m,2H), 2.07 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.0 (M+H),Rt. 2.26 min, 97.5% (Max). HPLC: (Method A) Rt. 2.21 min, 98.9% (Max).

Example 24:4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyrimidine

To a stirred solution of Intermediate 2 (0.2 g, 0.74 mmol) in DMF (5mL), TEA (0.5 mL, 3.70 mmol) and 4,6-dichloro pyrimidine (0.11 g, 0.74mmol) were added and the resulting mixture was stirred at 120° C. for 2h. It was concentrated under vacuum and the resulting crude product wasdissolved in DCM and washed with water, dried over anhydrous Na₂SO₄, andconcentrated under vacuum. The crude product was purified by flashchromatography to afford the title product (brown oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.30 (s, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.55-3.52 (m, 4H), 3.39-3.37(m, 1H), 2.43-2.39 (m, 2H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H).

LCMS: (Method A) 347.0 (M+H), Rt. 2.55 min, 98.7% (Max). HPLC: (MethodA) Rt. 2.57 min, 99.7% (Max).

Example 26:(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine or(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

The two enantiomers of Example 11 were separated by chiral preparativeHPLC (Method PF). The first eluting compound has Rt. 8.50 min (colorlessoil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H),6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H),5.97 (m, 2H), 3.68-3.67 (m, 4H), 3.37-3.35 (m, 1H), 2.49-2.38 (m, 2H),2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H),Rt. 2.45 min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.5% (Max).HPLC chiral purity: (Method D) Rt. 8.50 min, 100% (Max). Example 26 isthe second eluting compound, with Rt. 13.33 min (colorless oil). ¹H NMR(400 MHz, DMSO-d₆): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H), 6.83 (d,J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H), 5.97 (m,2H), 3.68-3.67 (m, 4H), 3.36-3.33 (m, 1H), 2.49-2.38 (m, 2H), 2.35-2.30(m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H), Rt. 2.44min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.8% (Max).

HPLC chiral purity: (Method D) Rt. 13.33 min, 100% (Max).

Example 27: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

Step 1: Ethyl 2-bromothiazole-5-carboxylate

To a stirred solution of ethyl-2-amino thiazole-5-carboxylate (10.0 g,46.45 mmol, Combi block) in 48% HBr (75 mL), sodium nitrite (4.80 g,69.68 mmol) in water (50 mL) was added dropwise at 0° C. and thereaction mixture was stirred at 0° C. for 15 min. Copper (I)bromide(6.66 g, 46.45 mmol) in 48% HBr (75 mL) was added dropwise at 0° C. andthe reaction mixture was stirred at rt for 4 h. The reaction mixture wasdiluted with DCM (200 mL) and washed with water (50 mL), brine (50 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (100% CHCl₃) to afford thetitle compound. Yield: 50.18% (5.5 g, yellow liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.16 (s, 1H), 4.38 (q, J=7.16 Hz, 2H), 1.40 (t, J=7.12 Hz,3H). LCMS: (Method A) 235.9 (M+H), Rt. 3.85 min, 98.6% (Max).

Step 2: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Intermediate 2 (1.5 g, 6.40 mmol) in dry DMF(15 mL), ethyl 2-bromothiazole-5-carboxylate (1.96 g, 8.32 mmol) and TEA(3.5 mL, 25.6 mmol) were added at rt and the reaction mixture wasstirred at 120° C. for overnight. The reaction mixture was cooled to rtand was diluted with EtOAc. The organic layer was washed with brine (10mL), water (10 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The crude product was purified by column chromatography toafford the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆):δ 7.83 (s, 1H), 6.89 (s, 1H), 6.89 (d, J=8.0 Hz, 1H). 6.76 (d, J=8.0 Hz,1H), 5.99 (s, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.50-3.42 (m, 5H), 2.51-2.46(m, 2H), 2.44-2.33 (m, 2H), 1.30-1.22 (m, 6H). LCMS: (Method A) 247.2(M+H), Rt. 3.17 min, 78.6% (Max).

Example 28:(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

The title compound was synthesized following the general procedure Astarting from Example 27. The crude product was purified by flashchromatography followed by MD Autoprep (Method B) (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 6.96 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 5.98 (m, 2H), 5.21 (t, J=5.6 Hz, 1H), 4.44(d, J=5.6 Hz, 2H), 3.40-3.37 (m, 1H), 3.34-3.31 (m, 4H), 2.46-2.42 (m,2H), 2.41-2.38 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 348.0(M+H), Rt. 1.91 min, 96.3% (Max). HPLC: (Method A) Rt. 1.89 min, 95.1%(Max).

Example 29:(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanol

The title compound was synthesized following general procedure A,starting with Example 17 (0.5 g) and the crude product was purified byflash chromatography (pale yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H), 6.52(s, 1H), 5.99 (m, 2H), 5.11-5.09 (t, J=8.0 Hz, 1H), 4.31 (d, J=8.0 Hz,2H), 3.40-3.34 (m, 5H). 2.51-2.49 (m, 2H), 2.42-2.32 (m, 2H), 1.28 (d,J=6.8 Hz, 3H). LCMS: (Method A) 348.0 (M+H), Rt. 1.98 min, 94.8% (Max).HPLC: (Method A) Rt. 1.99 min, 96.0% (Max).

Example 30:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

To a stirred solution of Example 18 (0.3 g, 0.5 mmol) in DCM (10 mL),DIPEA (0.6 mL, 2 mmol) and HATU (0.56 g, 1.48 mmol) were added slowly at0° C. The reaction mixture was stirred at 0° C. for 20 min. Methyl aminein THF (0.6 mL, 1.48 mmol) was added and the reaction mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, concentrated undervacuum. The crude product was purified by flash chromatography followedby MD Autoprep (Method B) to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, J=4.8 Hz, 1H), 7.33 (s,1H), 6.89 (s, 1H). 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H),5.98 (m, 2H), 3.43-3.38 (m, 5H), 2.72 (d, J=4.8 Hz, 3H), 2.41-2.39 (m,4H), 1.27 (d, J=6.4, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.34 min,98.2% (Max). HPLC: (Method A) Rt. 2.32 min, 99.0% (Max).

Example 32:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) andisopropyl amine (0.09 mL, 1.08 mmol) as starting material (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62 (d, J=8.4 Hz, 1H), 7.35 (s,1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.99(m, 2H), 4.04-3.99 (m, 1H), 3.43-3.34 (m, 5H), 2.50-2.42 (m, 4H), 1.29(d, J=6.8 Hz, 3H), 1.14-1.07 (m, 6H). LCMS: (Method A) 403.0 (M+H), Rt.2.90 min, 95.5% (Max). HPLC: (Method A) Rt. 2.91 min, 96.5% (Max).

Example 33:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-cyclohexylthiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) andcyclohexyl amine (0.12 mL, 1.08 mmol) as starting material (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J=8.4 Hz, 1H), 7.35 (s,1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.99(s, 2H), 3.68-3.67 (m, 1H), 3.42 (br.s, 4H), 2.50-2.42 (m, 4H),1.74-1.70 (m, 4H), 1.59-1.56 (m, 1H), 1.36-1.23 (m, 8H), 1.13-1.09 (m,1H). LCMS: (Method A) 443.0 (M+H), Rt. 3.57 min, 97.9% (Max). HPLC:(Method A) Rt. 3.62 min, 99.3% (Max).

Example 34:(R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidineor(S)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidine

The title compound was synthesized by following procedure D, usingIntermediate 3 (2.2 g, 11 mmol) and 1-(2-pyrimidyl) piperazine (1.8 g,11 mmol). The crude product was purified by flash chromatographyfollowed by preparative chiral HPLC (Method PF) to separate the twoenanatiomers. The first eluting compound has Rt. 7.90 min (Method D)(off white solid). ¹H NMR 400 MHz, DMSO-d₆): δ 8.32 (d, J=4.4 Hz, 2H),6.78-6.75 (m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.68-3.67(m, 4H), 3.36-3.26 (m, 1H), 2.49-2.39 (m, 2H), 2.34-2.32 (m, 2H), 1.25(d, J=6.4 Hz, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 2.51 min, 98.7%(Max). HPLC: (Method A) Rt. 2.54 min, 99.3% (Max). HPLC chiral purity:(Method D) Rt. 7.90 min, 100.0% (Max). Example 34 corresponds to thesecond eluting compound, with Rt. 13.92 min (Method D) (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=4.4 Hz, 2H), 6.80-6.75(m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.69-3.66 (m, 4H),3.33-3.32 (m, 1H), 2.44-2.38 (m, 2H), 2.36-2.31 (m, 2H), 1.26 (d, J=6.8Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.51 min, 99.1% (Max). HPLC:(Method A) Rt. 2.49 min, 99.2% (Max). HPLC chiral purity: (Method D) Rt.13.92 min, 99.88% (Max).

Example 35:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

The title compound was synthesized by following the same procedure asdescribed for

Example 30, using Example 18 (0.3 g, 0.9 mmol) and ammonia in THF (4.5mL, 9 mmol, 2 M in THF) as starting material. The crude mixture waspurified by flash chromatography (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.39 (br s, 2H), 7.37 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.99 (br s, 2H), 3.41-3.34 (m, 5H),2.50-2.43 (m, 4H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 361.0 (M+H),Rt. 2.19 min, 94.8% (Max). HPLC: (Method A) Rt. 2.17 min, 98.0% (Max).

Example 36:5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

The title compound was synthesized following general procedure D, using2-bromo-5-methyl thiazole and Intermediate 2. The crude product waspurified by flash chromatography (brown solid). ¹H NMR (DMSO-d₆): δ 6.89(s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.76-6.74 (m,1H), 5.99 (m, 2H), 3.40-3.36 (m, 1H), 3.29-3.26 (m, 4H), 2.46-2.45 (m,2H), 2.42-2.38 (m, 2H), 2.23 (s, 3H), 1.28-1.27 (m, 3H). LCMS: (MethodA) 332.0 (M+H), Rt. 2.13 min, 96.0% (Max). HPLC: (Method A) Rt. 2.11min, 97.4% (Max).

Example 37:5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

The mixture of 5-bromo-2-methyl thiazole (150 mg, 0.84 mmol),Intermediate 2 (200 mg, 0.84 mmol) and TEA (344 mg, 3.4 mmol) in DMF (4mL) was heated at 130° C. for overnight. It was concentrated undervacuum and to the resulting crude product was dissolved in EtOAc (10 mL)and washed with water (10 mL). The organic layer was dried over Na₂SO₄and concentrated. The crude product was purified by flash columnchromatography (brown solid). ¹H NMR (DMSO-d₆): δ 6.90 (s, 1H),6.85-6.78 (m, 3H), 5.95 (br s, 2H), 3.55-3.51 (m, 1H), 3.12-3.11 (m,4H), 2.80-2.65 (m, 4H), 2.54 (s, 3H), 1.44 (d, J=5.6 Hz, 3H). LCMS:(Method A) 332.0 (M+H), Rt. 5.71 min, 97.35% (Max). HPLC: (Method B) Rt.5.64 min, 96.8% (Max).

Example 38:5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2,5-dichloropyrimidine. The crude product waspurified by flash chromatography (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (m,J=8.0 Hz, 1H), 5.98 (m, 2H), 3.68-3.65 (m, 4H), 3.38-3.369 (m, 1H),2.44-2.39 (m, 1H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS:(Method A) 347.0 (M+H), Rt. 3.24 min, 98.3% (Max). HPLC: (Method A) Rt.3.22 min, 99.6% (Max).

Example 39:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methoxypyrimidine

The title compound was synthesized following general procedure D, usingIntermediate 2 and 2-chloro-5-methoxy pyrimidine. The crude product waspurified by flash chromatography (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.04 (d, J=5.6 Hz, 1H), 6.88-0 (s, 1H), 6.83 (d, J=8.0 Hz,1H), 6.74 (d, J=8.0 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 5.98 (br s, 2H),3.79 (s, 3H), 3.72-3.66 (m, 4H), 3.37-3.39 (m, 1H), 2.43-2.39 (m, 2H),2.34-2.30 (m, 2H), 1.28-1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 343.0(M+H), Rt. 2.27 min, 99.6% (Max). HPLC: (Method A) Rt. 2.27 min, 99.4%(Max).

Example 40:4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2,4-dichloropyrimidine. The crude product waspurified by flash chromatography (yellow oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.04 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz,1H), 6.80-6.75 (m, 2H), 5.99 (m, 2H), 3.59 (br.s, 4H), 3.39 (q, J=6.4Hz, 1H), 2.45-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.29-1.27 (d, J=6.8 Hz,3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min, 96.4% (Max). HPLC:(Method A) Rt. 2.51 min, 98.2% (Max).

Example 41:5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-5-bromo-1,3,4-thiadiazole. The crudeproduct was purified by recrystallisation. Yield: 81% (2.0 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88-6.87 (m, 1H), 6.85-6.83 (m,1H), 6.76-6.73 (m, 1H), 6.47 (s, 2H) 5.99 (s, 2H), 3.40-3.34 (m, 1H),3.19-3.17 (m, 4H), 2.47-2.43 (m, 2H), 2.40-2.36 (m, 2H), 1.27 (d, J=6.4Hz, 3H). LCMS: (Method A) 334.0 (M+H), Rt. 1.84 min, 96.5% (Max). HPLC:(Method A) Rt. 1.83 min, 98.2% (Max).

Example 42:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-4-carboxamide

The title compound was synthesized following the same procedure asdescribed for Example 30, using Example 18 (0.3 g, 0.9 mmol) anddimethyl amine (0.9 mL, 1.8 mmol, 2 M in THF) as starting material (paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.16 (s, 1H), 6.89 (s, 1H),6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.41-3.34 (m, 5H), 3.30 (s, 3H), 2.90 (s, 3H), 2.43-2.42 (m, 4H), 1.28(d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.41 min, 95.1%(Max). HPLC: (Method A) Rt. 2.38 min, 94.3% (Max).

Example 43:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

Step 1:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicAcid

To a stirred solution of Example 27 (0.8 g, 2.05 mmol) in dioxane (24mL), NaOH (2M in water, 3 mL) was added slowly. The reaction mixture wasstirred overnight at room temperature. It was then concentrated undervacuum and neutralized with HCl (1.5 N) up to pH=6 and was extractedwith DCM (25 mL). The organic layer was washed with water (15 mL), brine(15 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the title compound (off white solid). LCMS: (MethodA) 362.0 (M+H), Rt. 2.30 min, 77.6% (Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

To a solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (0.1 g, 0.277 mmol) in dry DCM (2 mL), HATU (0.16 g, 0.41 mmol) wasadded and the resulting mixture was stirred at room temperature for 1 h.Isopropyl amine (0.02 g, 0.36 mmol) and DIPEA (0.14 mL, 0.83 mmol) wereadded at 0° C. and the mixture was stirred overnight at roomtemperature. The reaction was quenched with water (10 mL) and extractedwith EtOAc (25 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated under vacuum. The resulting crude product was purifiedby MD Autoprep (Method B) to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (d, J=7.6 Hz, 1H), 7.78 (s,1H), 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99(br s, 2H), 3.98-3.96 (m, 1H), 3.42-3.41 (m, 5H), 2.42-2.38 (m, 4H),1.28 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 6H). LCMS: (Method A) 403(M+H), Rt. 2.72 min, 97.81% (Max). HPLC: (Method A) Rt. 2.70 min, 98.62%(Max).

Example 44:N-(5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Example 41 (0.06 g, 0.7 mmol),diisopropylethylamine (0.4 mL, 0.32 mmol) in dry DCM (4.0 mL), aceticanhydride (0.96 mL, 1.05 mmol) was added at 0° C. and the resultingmixture was stirred for 5 h at rt. The completion of the reaction wasmonitored by TLC. The reaction mixture was concentrated and the crudeproducts were purified by flash chromatography to afford the titlecompound (colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (m, 1H), δ6.89 (m, 1H), 6.86-6.84 (m, 1H), 6.77-6.75 (m, 1H), 5.99 (m, 2H),3.41-3.40 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.40 (m, 2H), 2.10 (s, 3H),1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.512 min,96.77% (Max). HPLC: (Method A) Rt. 2.262 min, 98.69% (Max).

Example 45:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

Step 1: 2-chloro-N-propylpyrimidin-4-amine

To a stirred solution of 2,4-dichloro pyrimidine (0.2 g, 1.34 mmol) indry THF (10 mL), TEA (0.54 g, 5.36 mmol) and propyl amine (0.088 g, 1.34mmol) were added and the resulting mixture was stirred at roomtemperature for 10 h. It was diluted with water and extracted withEtOAc. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford the title compound. Yield: 70% (0.18g, colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92-7.85 (m, 2H),6.49-6.41 (m, 1H), 3.21 (t, J=6.4 Hz 2H), 1.56-1.47 (m, 2H), 0.91-0.87(t, J=7.36 Hz, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 2.07 min, 99.5%(Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

To a stirred solution of Intermediate 2 (0.2 g, 0.9 mmol) in dry DMF(4.0 mL), 2-chloro-N-propylpyrimidin-4-amine (0.18 g, 1.04 mmol) and TEA(0.5 mL, 3.2 mmol) were added at 0° C. The reaction mixture was stirredat 130° C. for overnight. It was then concentrated and the crude productwas purified by flash chromatography to afford the title compound(colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (s, 1H), 6.89-6.75(m, 3H), 6.12-5.95 (m, 3H), 5.83 (br. s, 1H), 3.62 (m, 4H), 3.20 (s,3H), 2.51-2.49 (m, 4H), 1.50 (qm, 2H), 1.28-1.24 (m, 3H), 0.88 (t, J=8.0Hz, 3H). LCMS: (Method A) 370.0 (M+H), Rt. 2.604 min, 97.37% (Max).HPLC: (Method A) Rt. 2.54 min, 99.78% (Max).

Example 46:4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-4-chloropyrimidine. The crude productwas purified by flash chromatography (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.72 (d, 1H, J=6.0 Hz), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.95 (m, 5H), 3.46-3.45 (m, 4H),3.37-3.35 (m, 1H), 2.40-2.37 (m, 2H), 2.33-2.29 (m, 2H), 1.27 (d, J=6.4Hz, 3H). LCMS: (Method A) 328.0 (M+H), Rt. 1.86 min, 97.06% (Max). HPLC:(Method A) Rt. 1.81 min, 97.5% (Max).

Example 47:2-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (Example 43, Step 1, 0.155 g, 0.4 mmol) and HATU (0.206 g, 1.2mmol) in dry DMF (3 mL), DIPEA (0.1 mL, 0.8 mmol) was added and theresulting mixture was stirred for 30 min at room temperature.Dimethylamine in THF (0.5 mL, 8.4 mmol) was then added at 0° C. Thereaction mixture was stirred overnight at room temperature. Solventswere evaporated and the resulting crude mixture was diluted with EtOAc,washed with water, 10% sodium bicarbonate solution, brine and dried overNa₂SO₄. After evaporation of the solvents, the resulting crude productwas purified by MD Autoprep (Method B) to afford the title compound (offwhite solid). ¹H NMR (400 MHz, CDCl₃): δ 7.47 (s, 1H), 6.87 (s, 1H),6.77-6.76 (m, 2H), 5.96 (s, 2H), 3.52-3.51 (m, 4H), 3.37-3.36 (m, 1H),3.17 (s, 6H), 2.57-2.52 (m, 4H), 2.26 (s, 3H). LCMS: (Method B) 389(M+H), Rt. 5.049 min, 98.02% (Max). HPLC: (Method A) Rt. 2.42 min,98.49% (Max).

Example 48:2-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

To a solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylicacid (Example 43, Step 1, 0.15 g, 0.4 mmol) in dry DMF (3 mL), HATU(0.206 g, 1.2 mmol) was added and stirred at room temperature for 20min. Ammonia in THF (5 mL) and DIPEA (0.14 mL, 0.83 mmol) were thenadded at 0° C. The resulting reaction mixture was stirred at roomtemperature overnight. It was concentrated under reduced pressure. EtOAcwas added to the resulting mixture and was washed with water, 10% sodiumbicarbonate solution, brine and dried over Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by MD Autoprep (Method C)to afford the title compound (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.76 (s, 1H), 7.67 (br s, 1H), 7.11 (br s, 1H), 6.89 (s,1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (br s, 2H),3.41-3.40 (m, 5H), 2.50-2.39 (m, 4H), 1.28 (d, J=8.0 Hz, 3H). LCMS:(Method A) 361.0 (M+H), Rt. 2.01 min, 99.2% (Max). HPLC: (Method A) Rt.2.03 min, 98.5% (Max).

Example 49:2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

Step 1:Ethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

The title compound was synthesized following general procedure D, usingethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride (Example17, Step 2, 5.0 g, 20.4 mmol) and Intermediate 3 (4.97 g, 24 mmol). Thecrude product was purified by flash chromatography. Yield: 54% (4.5 g,black oil).

Step 2:2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicAcid

To a stirred solution ofethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate(4.5 g, 11.1 mmol) in THF (20 mL), 10% NaOH (50 mL) was added slowly.The reaction mixture was stirred at room temperature for overnight. Itwas concentrated under vacuum, neutralized with HCl (2 N in water) topH=6 and extracted with DCM (25 mL). The organic layer was washed withwater (10 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure afford the title compound (paleyellow solid). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (s, 1H), 6.94-6.76 (m,3H), 4.26 (s, 4H), 3.65-3.49 (m, 5H), 2.59-3.54 (m, 4H), 2.49-2.45 (m,4H), 1.26 (d, J=4.8 Hz, 3H), LCMS: (Method A) 376.0 (M+H), Rt. 2.36 min,79.7% (Max).

Step 3:2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

The title compound was synthesized according to the same procedure asdescribed for Example 30, using2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid and NH₃ in THF. The crude product was purified by flashchromatography (off white solid). ¹H NMR (400 MHz, DMSO-d₆): ¹H NMR (400MHz, DMSO-d₆): δ 7.39 (br s, 2H), 7.35 (s, 1H), 6.80-6.76 (m, 3H), 4.21(s, 4H), 3.38-3.38 (m, 5H), 2.49-2.45 (m, 4H), 1.27-1.23 (m, 3H). LCMS:(Method A) 375.0 (M+H), Rt. 2.21 min, 96.1% (Max). HPLC: (Method A) Rt.2.28 min, 96.6% (Max).

Example 50:2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The title compound was synthesized according to the same procedure asdescribed for Example 30, using2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylicacid and MeNH₂ in THF. The crude product was purified by flashchromatography (yellow oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.07 (q, J=4.0Hz, 1H), 7.33 (s, 1H), 6.76-6.39 (m, 3H), 4.21 (s, 4H), 3.38-3.32 (m,5H), 2.75-2.71 (m, 3H), 2.49-2.48 (m, 4H), 1.26-1.25 (m, 3H). LCMS:(Method A) 389.0 (M+H), Rt. 2.38 min, 95.9% (Max). HPLC: (Method A) Rt.2.46 min, 97.7% (Max).

Example 51: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

Step 1: tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine(6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at90° C. for 8 h. The reaction mixture was concentrated under reducedpressure. Water (50 mL) was added and the desired product was extractedwith DCM (150 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified byflash chromatography (10% EtOAc in pet ether) to afford the titlecompound. Yield: 76% (7 g, white). ¹H NMR (400 MHz, DMSO-d₆): δ 8.46 (s,2H), 3.68-3.67 (m, 4H), 3.39-3.37 (m, 4H), 1.40 (s, 9H). LCMS: (MethodA) 289.0 (M+H), Rt. 5.19 min, 99.05% (Max).

Step 2: 2-(4-(t-Butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylicAcid

To a stirred solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 g, 14.5 mmol) indry THF (50 mL), n-BuLi (13.5 mL, 21.7 mmol, 1.6 M in THF) was addeddropwise at −75° C. and stirred for 2 h at the same temperature. Dry CO₂gas was passed through the reaction mixture for 1 h. The reaction wasstirred for 30 min at same temperature and 30 min at rt. It was cooledto 0° C. and quenched by using 10% ammonium chloride solution. Theproduct was extracted with DCM (150 mL). The organic layer was washedwith water (50 mL), brine (50 mL) and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the title compound was isolated and used inthe next step without further purification. Yield: 55% (2.5 g, paleyellow oil). LCMS: (Method A) 308.0 (M+H), Rt. 3.61 min, 55.64% (Max).

Step 3: Ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate

To a stirring solution of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid(2.0 g, 6.0 mmol) in EtOH (250 mL), SOCl₂ (1.7 mL, 16.23 mmol) was addedslowly at 0° C. and the mixture was stirred at 90° C. for 15 h. It wasconcentrated under reduced pressure to afford the title compound (offwhite solid). LCMS: (Method A) 236 (M+H), Rt. 2.14, 49.8% (Max).

Step 4: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirring solution of ethyl2-(piperazin-1-yl)pyrimidine-5-carboxylate (2.5 g, 9.0 mmol),diisopropyl ethyl amine (5.9 mL, 27.0 mmol) in dry acetonitrile (50 mL),Intermediate 1 (2.08 g, 11.0 mmol) was added at rt and the reactionmixture was stirred at 80° C. overnight. The reaction mixture wasconcentrated under vacuum and the resulting crude product was purifiedby flash chromatography (50% EtOAC in pet ether) to afford the titlecompound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.75 (s, 2H), 6.90(s, 1H), 6.85-6.83 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.05 (d,J=2.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.28-4.23 (q, J=7.2 Hz, 2H),3.82-3.81 (m, 4H), 3.49 (q, J=6.8 Hz, 1H), 2.55-2.44 (m, 2H), 2.43-2.33(m, 2H), 1.29-1.24 (m, 6H). LCMS: (Method A) 385 (M+H), Rt. 3.23 min,94.1% (Max). HPLC: (Method A) Rt. 3.23 min, 99.14% (Max).

Example 52:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)methanol

The title compound was synthesized following general procedure A fromExample 51. The crude product was purified by flash chromatography (30%EtOAc in pet ether) to afford the title compound (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.27 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 5.05 (t, J=5.2 Hz, 1H), 4.30(d, J=5.2 Hz, 2H), 3.67 (s, 4H), 3.36-3.34 (m, 1H), 2.43-3.32 (m, 4H),1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.0 (M+H), Rt. 2.16 min,95.05% (Max). HPLC: (Method A) Rt. 2.11 min, 97.35% (Max).

Example 53:2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)pyrimidine

To a solution of 2-(piperazin-1-yl)pyrimidine (0.8 g, 4.8 mmol),diisopropylethylamine (3.0 mL, 5.7 mmol) in ACN (20 mL), Intermediate 5(1.04 g, 5.7 mmol) was added at rt and the resulting mixture was stirredovernight. It was diluted with water (5 mL) and extracted with DCM (2×50mL). The combined organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The crude product was purified by MD Autoprep (Method B)to afford the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.31 (d, J=4.8 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.67 (d,J=8.0 Hz, 1H), 6.58 (t, J=4.8 Hz, 1H), 4.48 (t, J=8.8 Hz, 2H), 3.67 (m,4H), 3.34 (t, J=6.8 Hz, 1H), 3.14 (m, 2H), 2.42-2.38 (m, 2H), 2.35-2.31(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 311.2 (M+H), Rt. 2.511min, 98.68% (Max).

HPLC: (Method A) Rt. 2.52 min, 99.82% (Max).

Example 54:N-(4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-yl)acetamide

To a stirred solution of Example 46 (0.35 g, 1.0 mmol) in dry DCM (3.5mL), pyridine (0.2 mL, 2.1 mmol), acetic anhydride (0.12 mL, 1.3 mmol)and DMAP (0.006 g, 0.5 mmol) were added at rt. The resulting mixture wasstirred for 5 h at rt and overnight at 50° C. It was diluted with ethylacetate (100 mL) and washed with HCl (1.5N), water, brine, dried overNa₂SO₄ and concentrated under vacuum. The resulting crude product waspurified by MD Autoprep (Method C) to afford the title compound (offwhite solid). ¹H NMR (400 MHz, MeOH-d₄): δ 7.99 (s, 1H), 6.88 (s, 1H),6.77 (s, 2H), 6.54 (br. s, 1H), 5.93 (s, 2H), 3.71 (s, 4H), 3.40 (q,J=6.8 Hz, 1H), 2.61-2.57 (m, 2H), 2.51-2.47 (m, 2H), 2.24 (s, 3H), 1.38(d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 1.88 min, 95.01%(Max). HPLC: (Method A) Rt. 1.83 min, 98.7% (Max).

Example 55:1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-nitropyridin-2-yl)piperazine

To a stirred solution of Intermediate 2 (0.2 g, 2.1 mmol), Et₃N (1.2 mL,8.5 mmol) in dry DMF (5 mL), 2-chloro-5-nitropyridine (0.44 g, 2.8 mmol)was added at rt. The resulting mixture was stirred at 120° C. for 20 h.The completion of the reaction was monitored by TLC. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (25 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude product was purified by flash chromatographyto afford the title compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆):δ 8.93 (d, J=2.8 Hz, 1H), 8.19 (dd, J=9.6, 2.8 Hz, 1H), 6.91-6.89 (m,2H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.73 (s, 4H), 3.40 (q, J=6.4 Hz, 1H), 2.41-2.38 (m, 4H), 1.29 (d, J=6.4Hz, 3H). LCMS: (Method A) 357.0 (M+H), Rt. 2.98 min, 96.03% (Max). HPLC:(Method A) Rt. 3.03 min, 95.35% (Max).

Example 56:(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamideor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The two enantiomers of Example 30 were separated by chiral preparativeHPLC (Method PG). The first eluting compound has a Rt. 15.74 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s,1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.42 (m, 5H), 2.72 (d, J=4.8 Hz, 3H),2.50-2.49 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375 (M+H),Rt. 2.35 min, 98.15% (Max). HPLC: (Method A) Rt. 2.38 min, 97.08% (Max),96.58% (254 nm). Chiral HPLC: (Method E) Rt. 15.74 min, 100.00%. Example56 corresponds to the second eluting compound, with Rt. 28.85 min (whitesolid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s,1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.41 (m, 5H), 2.72 (d, J=4.8 Hz, 3H),2.50-2.43 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H),Rt. 2.34 min, 99.94% (Max). HPLC: (Method A) Rt. 2.37 min, 99.77% (Max).Chiral HPLC: (Method E) Rt. 28.85 min, 100.00%

Example 57:(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamideor(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

The two enantiomers of Example 50 were separated by chiral preparativeHPLC (Method PG). The first eluting compound has a Rt. 16.29 min (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (q, J=4.4 Hz, 1H), 7.34 (s,1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.39 (m, 5H), 2.73 (d, J=4.8Hz, 3H), 2.48-2.41 (m, 4H), 1.27 (t, J=6.4 Hz, 3H). LCMS: (Method A).389.0 (M+H), Rt. 2.40 min, 99.14% (Max). HPLC: (Method A) Rt. 2.36 min,99.63% (Max). Chiral HPLC: (Method E) Rt, 16.29 min, 100% (max). Example57 corresponds to the second eluting compound, with Rt. 33.49 min(yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (d, J=4.4 Hz, 1H),7.34 (s, 1H), 6.81-6.74 (m, 3H), 4.21 (s, 4H), 3.42-3.37 (m, 5H), 2.73(d, J=4.8 Hz, 3H), 2.46-2.41 (m, 4H), 1.26 (t, J=6.4 Hz, 3H). LCMS:(Method A). 389.0 (M+H), Rt. 2.34 min, 98.58% (Max). HPLC: (Method A)Rt. 2.37 min, 99.28% (Max). Chiral HPLC: (Method E) Rt. 33.49 min,99.66% (max).

Example 58:6-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-amine

To a stirred solution of Example 55 (0.20 g, 5.6 mmol) in methanol (4.0mL), Pd/C (0.02 g, 10% w/w) was added at rt and the mixture was stirredovernight under hydrogen atmosphere (5 Kg/cm²) at rt. The reactionmixture was filtered through celite and washed with methanol (10 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulted crude product was purified by MD Autoprep (MethodC) to afford the title compound (dark oil). ¹H NMR (400 MHz, DMSO-d₆): δ7.57 (d, J=2.8 Hz, 1H), 6.90-6.88 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.76(d, J=8.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.98 (m, 2H), 4.55 (s, 2H),3.33 (br m, 1H), 3.18 (s, 4H), 2.38-2.36 (m, 4H), 1.27 (d, J=6.4 Hz,3H). LCMS: (Method A) 327.2 (M+H), Rt. 1.85 min, 98.76% (Max). HPLC:(Method A) Rt. 1.81 min, 99.66% (Max).

Example 59 and Example 60:(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

Step 1: Lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Example 27 (1.8 g, 3.86 mmol) in THF (14 mL)MeOH (4 mL) and H₂O (2 mL) was added LiOH.H₂O (395 mg, 9.65 mmol). Thereaction mixture was stirred at 50° C. for 3 h. The completion of thereaction was monitored by TLC. The reaction mixture was concentratedunder vacuum. The resulting crude product was suspended in toluene andthe solvents were evaporated again. It was used in the next step withoutany further purification. Yield: 89% (1.5 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.73 (s, 1H), 6.88-6.82 (m, 2H), 6.75-6.73 (m,1H), 5.97 (s, 2H), 3.67-3.32 (m, 5H), 2.87-2.59 (m, 4H), 1.32-1.15 (m,3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.26 min, 88.6% (Max).

Step 2:(R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

To a stirred solution of lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(500 mg, 1.33 mmol) in DMF (10 mL), DIPEA (0.7 mL, 3.99 mmol), ethylamine (2 M in THF, 1 mL, 2.00 mmol) and HATU (607 mg, 1.60 mmol) wereadded at 0° C. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under vacuum anddiluted with DCM. It was washed with water, brine and dried overanhydrous Na₂SO₄. The crude product was purified by flashchromatography. Both enantiomers were separated by chiral preparativeHPLC (Method PF). Example 59 corresponds to the first eluting compoundwith a Rt. 17.99 min (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19(t, J=5.6 Hz, 1H), 7.74 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H),6.76 (d, J=6.4 Hz, 1H), 5.99 (s, 2H), 3.21-3.17 (m, 2H), 2.48-2.39 (m,4H), 1.28 (d, J=6.4 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A)389.2 (M+H), Rt. 2.47 min, 97.4% (Max). HPLC: (Method A) Rg. 2.43 min,99.9% (Max). Chiral HPLC: (Method D) Rt. 17.99 min, 100.00%. Example 60corresponds to the second eluting compound with a Rt. 19.92 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (t, J=5.6 Hz, 1H), 7.74 (s,1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=6.8 Hz, 1H), 5.99(s, 2H), 3.21-3.17 (m, 2H), 2.48-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H),1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.46 min,99.3% (Max). HPLC: (Method A) Rt. 2.43 min, 99.9% (Max). Chiral HPLC:(Method D) Rt. 19.92 min, 100.00%.

Example 61:(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamideor(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

The two enantiomers of Example 47 were separated by chiral preparativeHPLC (Method PF). The first eluting compound has a Rt. 14.07 min (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85(s, 1H), 6.76 (s, 1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H),2.47-2.39 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H),Rt. 2.39 min, 99.5% (Max). HPLC: (Method A) Rt. 2.37 min, 99.6% (Max).Chiral HPLC: (Method D) Rt. 14.07 min, 100.00%. Example 61 correspondsto the second eluting compound with Rt. 16.06 min (white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.76 (s,1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H), 2.50-2.39 (m,4H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.44 min,95.3% (Max). HPLC: (Method A) Rt. 2.37 min, 99.9% (Max). Chiral HPLC:(Method D) Rt. 16.06 min, 99.7%.

Example 62:(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideor(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

Step 1: Ethyl2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

To a stirred solution of Intermediate 4 (3.4 g, 11.94 mmol) in dry DMF(50 mL), ethyl 2-bromothiazole-5-carboxylate (Example 27, Step 1, 2.8 g,11.94 mmol) and TEA (5.0 mL, 35.82 mmol) were added at 0° C. Theresulting mixture was stirred at 120° C. overnight. It was cooled to rt,diluted with EtOAc, washed with water, brine, dried over anhydrousNa₂SO₄ and concentrated under vacuum. The resulting crude product waspurified by flash chromatography to afford the title compound. Yield:64% (3.1 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s,1H), 6.79-6.74 (m, 3H), 4.19-4.14 (m, 7H), 3.48-3.32 (m, 4H), 2.42-2.36(m, 4H), 1.26-1.19 (m, 6H). LCMS: (Method A) 404.0 (M+H), Rt. 3.19 min,96.5% (Max).

Step 2: Lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

The title compound was synthesized according to the protocol describedfor Example 60, Step 1, using ethyl2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylateas starting material. The resulting product was used in the next stepwithout further purification. Yield: 86% (2.5 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.16 (s, 1H), 6.79-6.72 (m, 3H), 4.20 (s, 4H),3.34-3.29 (m, 5H), 2.44-2.28 (m, 4H), 1.24 (d, J=8.8 Hz, 3H). LCMS:(Method A) 376.0 (M+H), Rt. 2.34 min, 97.4% (Max).

Step 3:(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamideor(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

The title compound was synthesized according to the protocol describedfor Example 60, Step 2, using lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylateas starting material. The crude mixture was purified by flashchromatography followed by chiral preparative HPLC (Method PE) toseparate both enantiomers. The first fraction was concentrated to giveExample 62 (Rt. 19.00 min) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.19 (t, J=5.2 Hz, 1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H),3.42-3.35 (m, 5H), 3.22-3.16 (m, 2H), 2.50-2.33 (m, 4H), 1.27 (d, J=6.8Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.50min, 98.4% (Max). HPLC: (Method A) Rt. 2.47 min, 98.2% (Max). ChiralHPLC: (Method A) Rt. 19.00 min, 100%. The second enantiomer had a Rt.29.37 min (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (t, J=5.6 Hz,1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.37 (m, 5H),3.22-3.17 (m, 2H), 2.50-2.41 (m, 4H), 1.27 (d, J=6.4 Hz, 3H), 1.07 (t,J=7.2 Hz, 3H). LCMS: (Method A) 403.2 (M+H), Rt. 2.51 min, 99.6% (Max).HPLC: (Method A) Rt. 2.47 min, 98.9% (Max). Chiral HPLC: (Method A) Rt.29.37 min, 100%.

Example 63 and Example 64:(R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamideand(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

The title compounds were synthesized according to the protocol describedfor Example 59 and Example 60, Step 2, using lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(Example 62, Step 2) and dimethyl amine as starting material. The crudemixture was purified by flash chromatography. Both enantiomers wereseparated by chiral preparative HPLC (Method PF). The first fractioncorresponds to Example 63 (Rt. 17.78 min) (white solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.81-6.75 (m, 3H), 4.22 (s, 4H),3.44-3.38 (m, 5H), 3.06 (br. s, 6H), 2.47-2.39 (m, 4H), 1.27 (d, J=6.8Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.42 min, 99.3% (Max). HPLC:(Method A) Rt. 2.41 min, 99.6% (Max). Chiral HPLC: (Method D) Rt. 17.78min, 100.00%. The second fraction corresponds to Example 64 (Rt. 21.09min) (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.58 (s, 1H), 6.81-6.77(m, 3H), 4.22 (s, 4H), 3.44-3.38 (m, 5H), 3.12-2.99 (m, 6H), 2.46-2.39(m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.43min, 99.8% (Max). HPLC: (Method A) Rt. 2.40 min, 99.8% (Max). ChiralHPLC: (Method D) Rt. 21.09 min, 97.38%.

Example 65 and Example 66:(R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamideand(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

The title compounds were synthesized according to the proceduredescribed for Example 59 and Example 60 using methyl amine (2M in THF)as reagent. The crude mixture was purified by flash chromatographyfollowed by chiral preparative HPLC (Method PF) to separate enantiomers.The first fraction was concentrated to give Example 65 (white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.16 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 6.89 (s,1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H),3.43-3.42 (m, 5H), 2.69 (d, J=4.4 Hz, 3H), 2.47-2.33 (m, 4H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 99.0% (Max).HPLC: (Method A) Rt. 2.19 min, 99.6% (Max). Chiral HPLC: (Method D) Rt.15.48 min, 98.91%.

The second fraction was concentrated to give Example 66 (white solid).¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (q, J=4.8 Hz, 1H), 7.72 (s, 1H), 6.90(s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s,2H), 3.43-3.41 (m, 5H), 2.69 (d, J=4.8 Hz, 3H), 2.48-2.39 (m, 4H), 1.28(d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 97.4%(Max). HPLC: (Method A) Rt. 2.19 min, 96.9% (Max). Chiral HPLC: (MethodD) Rt. 18.44 min, 100.00%

Example 67:(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(morpholino)methanone

The title compound was synthesized according to the procedure describedfor Example 59 and Example 60 using morpholine as reagent. Bothenantiomers were not separated in this example (pale brown solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.55 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz,1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (s, 2H), 3.61 (br m, 8H), 3.45-3.42(m, 5H), 2.47-2.40 (m, 4H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A)431.0 (M+H), Rt. 2.41 min, 98.6% (Max). HPLC: (Method A) Rt. 2.38 min,97.1% (Max).

Example 68 and Example 69:(R)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideand(S)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Example 41 (0.6 g, 1.8 mmol) in dry DCM (10mL), acetic anhydride (0.22 mL, 2.3 mmol) and DIPEA (0.615 mL, 3.6 mmol)were added at 0° C. and the reaction mixture was stirred at roomtemperature for 4 h. It was concentrated under vacuum and the crudeproduct was purified by recrystallization followed by enantiomerseparation by SFC. The first fraction was collected as Example 68 (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.66 (br s, 1H), 6.89 (s,1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (m, 2H),3.42-3.34 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.33 (m, 2H), 2.09 (s, 3H),1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.27 min,97.4% (Max). HPLC: (Method A) Rt. 2.29 min, 98.2% (Max). HPLC chiralpurity: (Method D) Rt. 24.02 min, 99.3% (Max). The second fraction wascollected as Example 69 (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.66 (br s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.2 Hz, 1H), 5.99 (m, 2H), 3.41-3.34 (m, 5H), 2.55-2.47 (m, 2H),2.43-2.39 (m, 2H), 2.09 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 376.0 (M+H), Rt. 2.28 min, 95.8% (Max). HPLC: (Method A) Rt. 2.29min, 97.1% (Max). HPLC chiral purity: (Method D) Rt. 26.57 min, 97.5%(Max).

Alternatively, Example 69 can be synthesized according to the followingprotocol:

Example 69:(S)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

To a stirred solution of Example 132 (102.0 g, 305.9 mmol) in THF (500mL), pyridine (120.8 g, 1529.9 mmol) and acetic anhydride (33.9 g, 333.0mmol) were added at 0° C. and the resulting mixture was stirred at rtfor 1.0 h. Completion of the reaction was confirmed by TLC. Reactionmixture was evaporated under vacuum at 50° C. Water (200 mL) was addedand the resulting suspension was stirred for 15 min at rt and filtered.The filtration cake was washed with water (2×100 mL), hexane (2×200 mL)and Et₂O (2×200 mL). The crude product was heated in Et₂O (500 mL),cooled down to rt and filtered. The filtration cake was washed with Et₂O(100 mL) and dried under vacuum at 40° C. to afford the title compound.Yield: 67% (76.0 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.01(s, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.74 (dd,J=7.9, 1.0 Hz, 1H), 5.98-5.97 (m, 2H), 3.38 (q, J=6.7 Hz, 1H), 3.34-3.31(m, 4H), 2.49-2.40 (m, 4H), 2.01 (s, 3H), 1.26 (d, J=6.7 Hz, 3H). ¹³CNMR (400 MHz, DMSO-d₆): δ168.2, 167.7, 150.6, 147.7, 146.5, 137.5,121.0, 108.2, 108.0, 101.2, 63.7, 49.6, 49.6, 49.3, 49.3, 22.6, 19.7.LCMS: (Method A) 376.0 (M+H), Rt. 2.37 min, 99.56% (Max), 99.35% (254nm). HPLC: (Method A) Rt. 2.20 min, 99.65% (Max), 99.34% (254 nm).Chiral HPLC: (Method D) Rt. 26.87 min, 100%. Optical Rotation: [α]²⁸_(D) −59.78, c 1.0 (CHCl₃). Melting Point: 220.8-221.8° C.

The invention also relates to a compound of formula 69, having achemical purity of higher than 98%, preferably higher than 99%, evenmore preferably higher than 99.5% and/or an enantiomeric excess ofhigher than 98%, preferably higher than 99%, even more preferably higherthan 99.5%. The physical data of such compound are presented in FIGS. 7,8, 9 and 10 of this application.

Example 70:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

Step 1:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

To a stirred solution of Intermediate 2 (1 g, 4.2 mmol) in dry DMF (10mL), Et₃N (2.3 mL, 16.8 mmol) and 2-chloro-5-nitropyrimidine (0.74 g,4.6 mmol) were added at rt and the resulting mixture was stirred at 120°C. for 20 h. It was diluted with water and extracted with EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The resulting crude product was purified by flash chromatographyto give the title compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ9.08 (s, 2H), 6.92 (s, 1H), 6.85-6.83 (m, 1H), 6.77 (s, 1H), 5.98 (m,2H), 3.89 (s, 4H), 3.50 (s, 1H), 2.45-2.44 (m, 4H), 1.30 (br s, 3H).LCMS: (Method A) 358.0 (M+H), Rt. 3.00 min, 94.23% (Max).

Step 2:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine(0.70 g, 1.9 mmol) in methanol (14 mL), Pd/C (0.07 g, 10% w/w) was addedat rt and the resulting mixture was stirred under hydrogen atmosphere (5kg/cm²) overnight at rt. The reaction mixture was filtered throughcelite and washed with methanol. The filtrate was dried over anhydrousNa₂SO₄ and concentrated under vacuum. The crude product was purified byflash chromatography to afford the title compound (yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.86 (s, 2H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.46 (s, 2H), 5.98 (m, 2H), 3.48-3.45 (m,4H), 2.43-2.42 (m, 2H), 2.34-2.31 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS:(Method A) 328.2 (M+H), Rt. 1.91 min, 96.83% (Max). HPLC: (Method A) Rt.1.88 min, 95.85% (Max).

Example 71:(R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamideor(S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamide

The title compound was synthesized according to the procedure describedfor Example 62, using N,N,N trimethyl ethylene diamine as reagent. Thecrude product was purified by flash chromatography, followed by chiralpreparative HPLC using (Method PF) to separate both enantiomers. Thefirst eluting compound had Rt. 14.56 min (pale brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 7.57 (s, 1H), 6.80-6.73 (m, 3H), 4.21 (s, 4H), 3.52 (t,J=6.4 Hz, 2H), 3.50-3.38 (m, 5H), 3.16-3.11 (m, 3H), 2.56-2.50 (m, 1H),2.49-2.38 (m, 5H), 2.32-2.10 (m, 6H), 1.26 (d, J=6.8 Hz, 3H). LCMS:(Method A) 460.2 (M+H), Rt. 2.12 min, 95.2% (Max). HPLC: (Method A) Rt.2.02 min, 96.9% (Max). Chiral HPLC: (Method D) Rt. 14.56 min, 97.43%.The second eluting compound corresponds to Example 71 (Rt. 16.81 min)(pale brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.56 (s, 1H), 6.80-6.73(m, 3H), 4.21 (s, 4H), 3.50 (t, J=6.8 Hz, 2H), 3.48-3.36 (m, 5H), 3.09(br. s, 3H), 2.55-2.50 (m, 1H), 2.49-2.38 (m, 5H), 2.13 (s, 6H), 1.26(d, J=6.8 Hz, 3H). LCMS: (Method A) 460.2 (M+H), Rt. 2.13 min, 95.4%(Max). HPLC: (Method A) Rt. 2.03 min, 97.5% (Max). Chiral HPLC: (MethodD) Rt. 16.81 min, 98.36%.

Example 72:N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Example 70 (180 mg, 0.54 mmol) in dry pyridine(1.35 mL), acetic anhydride (0.06 mL, 0.65 mmol) was added at roomtemperature and the resulting mixture was stirred at 50° C. overnight.It was diluted with ethyl acetate (100 mL) and washed with HCl (1.5 N),water, brine and dried over Na₂SO₄. After evaporation of the solvents,the crude product was purified by flash chromatography to afford thetitle compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.82 (s,1H), 8.46 (d, J=0.4 Hz, 2H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76(d, J=7.6 Hz, 1H), 5.98 (m, 2H), 3.64-3.62 (m, 4H), 3.36-3.34 (m, 1H),2.45-2.32 (m, 4H), 2.00 (s, 3H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 370.2 (M+H), Rt. 2.30 min, 94.42% (Max). HPLC: (Method A) Rt. 2.22min, 95.29% (Max).

Example 73:(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

Step 1:1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one

The title compound was synthesized according to the same procedure asdescribed for Example 62 using piperidine-4-one, hydrochloride, monohydrate as starting material (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.61 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.89 (t,J=6.1 Hz, 4H), 3.71 (t, J=6.1 Hz, 1H), 3.60 (t, J=4.2 Hz, 4H), 2.34-2.33(m, 8H), 1.27 (d, J=6.7 Hz, 3H). LCMS: (Method A) 457.0 (M+H), Rt. 2.42min, 90.5% (Max).

Step 2:(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

To a stirred solution of1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one(480 mg, 1.0 mmol) in dry MeOH (100 mL), NaBH₄ (59 mg, 1.5 mmol) wasadded slowly at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. It was then concentrated under vacuum and theresulting crude product was dissolved in DCM, washed with water, brineand dried over anhydrous Na₂SO₄. The solvent was removed under reducedpressure to get the title compound. Yield: 69% (325 mg, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (s, 1H), 6.80-6.73 (m, 3H),4.78 (br. s, 1H), 4.21 (s, 4H), 3.92-3.88 (m, 2H), 3.72 (br s, 1H),3.42-3.35 (m, 4H), 3.33-3.25 (m, 2H), 2.46-2.38 (m, 4H), 1.75-1.74 (m,2H), 1.34-1.31 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 459.0(M+H), Rt. 2.32 min, 95.8% (Max). HPLC: (Method A) Rt. 2.33 min, 97.7%(Max).

Example 74 and Example 75:(R)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanoneand(S)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanone

The title compounds were synthesized according to the same procedure asdescribed for Example 62, using N-methyl piperazine as startingmaterial. The crude mixture was purified by column chromatographyfollowed by chiral preparative HPLC using (Method PF) to separate bothenantiomers. The first eluting fraction was concentrated to give Example74 (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (s, 1H),6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.60 (br. s, 4H), 3.43-3.38 (m, 5H),2.45-2.33 (m, 8H), 2.19 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 458.2 (M+H), Rt. 2.02 min, 99.2% (Max). HPLC: (Method A) Rt. 2.01min, 99.7% (Max). Chiral HPLC: (Method D) Rt. 14.95 min, 98.36%. Thesecond eluting fraction was concentrated to give Example 75 (pale brownoil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (s, 1H), 6.81-6.74 (m, 3H), 4.22(s, 4H), 3.60-3.59 (m, 4H), 3.43-3.37 (m, 5H), 2.50-2.31 (m, 8H), 2.19(s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 458.2 (M+H), Rt. 2.02min, 98.3% (Max). HPLC: (Method A) Rt. 2.01 min, 99.2% (Max). ChiralHPLC: (Method D) Rt. 17.10 min, 97.39%.

Example 77 and Example 78:(R)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamideand(S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

Example 72 was submitted to chiral preparative HPLC (Method PD). Thefirst eluting fraction was concentrated, affording Example 77 (paleyellow solid). ¹H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.46 (s, 2H),6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m,2H), 3.63 (t, J=4.8 Hz, 4H), 3.31 (s, 1H), 2.44-2.33 (m, 4H), 2.00 (s,3H), 1.26 (d, J=6.0 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.33 min,99.5% (Max). HPLC: (Method A) Rt. 2.24 min, 99.7% (Max). Chiral HPLC:(Method F) Rt. 31.24 min, 99.05%. The second eluting fraction wasconcentrated, affording Example 78 (pale yellow solid). 1H NMR (400 MHz,DMSO-d₆: δ 9.81 (s, 1H), 8.46 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.63 (t, J=4.8 Hz, 4H), 3.31(s, 1H), 2.41-2.32 (m, 4H), 2.00 (s, 3H), 1.26 (d, J=6.0 Hz, 3H). LCMS:(Method A) 370.2 (M+H), Rt. 2.31 min, 99.5% (Max). HPLC: (Method A) Rt.2.25 min, 99.8% (Max). Chiral HPLC: (Method F) Rt. 21.26 min, 100.00%.

Example 79:4-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

Step 1:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

To a stirred solution of Example 27 (6.0 g, 16.4 mmol) in dry THF (70mL), Super hydride (65 mL, 65.0 mmol) was added slowly at 0° C. Thereaction mixture was stirred at rt for 2 h. The reaction mixture wasquenched with saturated NH₄Cl and extracted with ethyl acetate. Theorganic layer was separated, dried over anhydrous Na₂SO₄, concentratedunder vacuum. The crude product was purified by silica gel columnchromatography (10% MeOH in DCM) to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.93 (s, 1H), 6.87-6.84 (d, J=12.8Hz, 1H), 6.81-6.75 (m, 1H), 6.74-6.72 (d, J=8.8 Hz, 1H), 5.96-5.96 (d,J=1.2 Hz, 2H), 5.18-5.16 (d, J=7.8 Hz, 1H), 3.41-3.28 (m, 3H), 2.52-2.37(m, 8H), 2.25 (s, 1H). LCMS: (Method A) 348.0 (M+H), Rt. 1.95 min,97.02% (Max).

Step 2:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole

To a stirred solution of(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol(4.0 g, 11.5 mmol) in DCM (50 mL), SOCl₂ (1.6 mL, 23.0 mmol) was addedslowly at 0° C. and the resulting mixture was stirred at rt for 1 h. Itwas concentrated under vacuum. The resulting crude product was taken fornext step reaction without further purification. Yield: 96% (4.8 g,Yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.69 (s, 1H), 7.36-7.33 (m,1H), 7.13-6.98 (m, 2H), 6.07 (s, 2H), 4.46 (d, J=12.8 Hz, 2H), 4.04-3.69(m, 4H), 3.54-3.27 (m, 1H), 3.12-292 (m, 3H), 1.69 (d, J=6.0 Hz, 3H).LCMS: (Method A) 363 (M+H), Rt. 2.49 min, 86.01% (Max).

Step 3:4-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole(0.8 g, 2.0 mmol) in dry ACN (20 mL), DIPEA (1.8 mL, 8.0 mmol) andmorpholine (0.22 mL, 2.4 mmol) were added and the reaction mixture wasstirred at rt overnight. The reaction mixture was diluted with EtOAc andwashed with water. It was dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The crude product was purified by flash chromatography(10% MeOH in DCM) to afford the title compound (pale yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 6.95 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz,1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 3.54-3.53 (m, 4H), 3.48 (s,2H), 3.39 (q, J=6.8 Hz, 1H), 3.25-3.40 (m, 4H), 2.40-2.33 (m, 4H),1.28-1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 418.0 (M+H), Rt. 1.99 min,97.82% (Max). HPLC: (Method A) Rt. 1.78 min, 95.19% (Max).

Example 80:N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)-N-methylacetamide

Step 1:1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole(Example 79, Step 3, 1.2 g, 3.1 mmol) in dry ACN (20 mL), DIPEA (2.3 mL,12.4 mmol) and methyl amine (5.0 mL, 9.3 mmol, 2 M in THF) were addeddropwise. The resulting mixture was stirred at rt overnight. It wasdiluted with water and extracted with ethyl acetate. The organic layerwas separated, dried over anhydrous Na₂SO₄, concentrated under vacuum.The crude product was purified by flash chromatography (10% MeOH in DCM)to afford the title compound (yellow solid). LCMS: (Method A) 362.0(M+H), Rt. 1.96 min, 25.6% (Max).

Step 2:N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)-N-methylacetamide

To a stirred solution of1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine(0.1 g, 0.27 mmol), DIPEA (0.3 mL, 0.8 mmol) in dry DCM (10 mL), aceticanhydride (0.3 mL, 0.8 mmol) was added portion wise and the reactionmixture was stirred at rt for 12 h. It was quenched with water (10 mL)and extracted with ethyl acetate (25 mL). The organic layer was driedover anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crudeproduct was purified by flash chromatography (10% MeOH in DCM) to affordthe title compound (pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ7.05 (d, J=9.6 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d,J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.40 (s, 2H), 3.39 (q, J=6.0 Hz, 1H),3.33-3.30 (m, 4H), 2.88 (s, 3H), 2.50-2.37 (m, 4H), 1.97 (s, 3H), 1.27(d, J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.19 min, 97.19%(Max). HPLC: (Method A) Rt. 2.14 min, 98.5% (Max).

Example 81:(R)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanoneor(S)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

The two enantiomers of Example 73 were separated by chiral preparativeHPLC, (Method PH). The first eluting compound had Rt. 32.84 min (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.49 (s, 1H), 6.79-6.77 (m,3H), 4.78 (br. s, 1H), 4.22 (s, 4H), 3.93-3.90 (m, 2H), 3.73-3.72 (m,1H), 3.42-3.38 (m, 5H), 3.34-3.28 (m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74(m, 2H), 1.38-1.26 (m, 5H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min,95.9% (Max). HPLC: (Method A) Rt. 2.21 min, 94.4% (Max). Chiral HPLC:(Method B) Rt. 32.84 min, 100%. The second eluting compound was isolatedas Example 81 with Rt. 36.77 min (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.49 (s, 1H), 6.80-6.74 (m, 3H), 4.78 (br. s, 1H), 4.22 (s,4H), 3.94-3.88 (m, 2H), 3.74-3.72 (m, 1H), 3.43-3.38 (m, 5H), 3.33-3.26(m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74 (m, 2H), 1.36-1.32 (m, 2H), 1.27(d, J=6.4 Hz, 3H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min, 98.9%(Max). HPLC: (Method A) Rt. 2.23 min, 99.8% (Max). Chiral HPLC: (MethodB) Rt. 36.77 min, 94.52%.

Example 84:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

Step 1:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole

To a stirred solution of Example 29 (1 g, 2.88 mmol) in dry DCM at 0°C., thionylchloride (0.4 mL, 8.64 mmol, spectrochem) was added dropwise.The reaction mixture was stirred at rt for 2 h. It was then concentratedand the resulting crude product was used without further purification.Yield: quantitative (1.2 g, pink solid). ¹H NMR (400 MHz, DMSO-d₆): δ7.73-7.35 (m, 1H), 7.31-6.95 (m, 2H), 6.05 (s, 2H), 5.74 (s, 1H),5.01-4.96 (m, 1H), 4.46 (s, 1H), 3.97-3.58 (m, 4H), 3.35-3.07 (m, 4H),1.21 ((d, J=8.8 Hz, 3H). LCMS: (Method A) 362.0 (M−H), Rt. 2.45 min,77.9% (Max).

Step 2:4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

To a stirred solution of2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole(1.2 g, 3.28 mmol) in dry DCM at 0° C., sodium azide (0.32 g, 4.9 mmol,spectrochem) was added in portion. The resulting mixture was heated at80° C. for 12 h. It was then concentrated. The residue was dissolved inDCM (50 mL), washed with water (15 mL) and dried over Na₂SO₄. Afterevaporation of the solvents, the crude product was used without furtherpurification. Yield: (1.1 g, colorless liquid). LCMS: (Method A) 373.0(M+H), Rt. 2.96 min, 78.9% (Max).

Step 3:(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

To a stirred solution of4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole(1.1 g, 2.95 mmol) in THF (18 mL) and water (2 mL), triphenylphosphine(1.16 g, 4.4 mmol, spectrochem) was added in portion and the resultingmixture was heated at 60° C. for 12 h. The reaction mixture wasconcentrated in a vacuum. The residue was dissolved in DCM (25 mL),washed with water (10 mL) and dried over Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by MD Autoprep (Method B)(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (t, J=2.4 Hz, 2H),6.86-6.83 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.70 (s, 2H),3.40 (t, J=6.8 Hz, 1H), 3.33-3.28 (m, 4H), 2.42-2.37 (m, 4H), 1.90 (s,2H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min,98.65% (Max). HPLC: (Method A) Rt. 1.86 min, 98.9% (Max).

Example 85:N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methyl)acetamide

To a solution of Example 84 (0.08 g, 0.23 mmol) in dry dichloromethane(5 mL), pyridine (0.01 mL, 0.11 mmol, spectrochem) and acetic anhydride(0.01 mL, 0.11 mmol, spectrochem) were added and the resulting mixturewas stirred at rt for 12 h. It was concentrated. The crude residue wasdissolved in DCM (15 mL), washed with water (5 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep (Method C) (off white solid). ¹H NMR (400 MHz,CDCl3): δ 7.00 (s, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 5.97 (s, 2H), 5.77(s, 1H), 4.43 (d, J=4.6 Hz, 2H), 3.48 (t, J=3.6 Hz, 5H), 2.56 (s, 4H),2.00 (s, 3H), 1.41 (s, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.02 min,94.37% (Max). HPLC: (Method A) Rt. 1.94 min, 92.8% (Max).

Example 86:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

Step 1:5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amine

The title compound was synthesized following the general procedure D,using Intermediate 2 and 2-amino-5-bromo thiazole, hydrobromide salt asstarting materials. Yield: 66% (0.85 g, black solid). LCMS: (Method A)333.0 (M+H), Rt. 1.99 min, 57.8% (Max).

Step 2:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

The title compound was synthesized via same procedure as described forExample 44, using5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amineas starting material (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.68 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz,1H), 6.57 (s, 1H), 5.99 (s, 2H), 3.38-3.33 (m, 1H), 3.02-2.92 (m, 4H),2.50-2.43 (m, 4H), 2.06 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 375.0 (M+H), Rt. 2.49 min, 97.9% (Max). HPLC: (Method A) Rt. 2.41min, 97.5% (Max).

Example 96:N-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

To a stirred solution of Intermediate 10 (320 mg, 1.24 mmol) in dry ACN(5 mL), DIPEA (3.66 mL, 20.28 mmol) and Intermediate 3 (270 mg, 1.36mmol) were added and the reaction mixture was stirred at 80° C.overnight. It was concentrated under vacuum and the crude product wasdissolved in EtOAc (30 mL), washed with water (10 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to afford the title compound (paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.79 (s, 1H), 8.44 (s, 2H),6.76-6.74 (m, 3H), 4.19 (s, 4H), 3.61 (s, 4H), 2.38-2.31 (m, 4H), 1.98(s, 3H), 1.24 (d, J=6.4 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.27min, 99.82% (Max). HPLC: (Method A) Rt. 2.26 min, 98.35% (Max).

Example 97:N-(5-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the same procedure asExample 96, using Intermediate 7 and Intermediate 3 as startingmaterials. The crude product was purified by flash chromatographyfollowed by MD Autoprep (Method B) to give the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 6.80-6.74 (m, 3H),4.21 (s, 4H), 3.37-3.33 (m, 5H), 2.43-2.39 (m, 4H), 2.09 (s, 3H), 1.26(d, J=6.8 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.39 min, 98.62%(Max). HPLC: (Method A) Rt. 2.27 min, 97.05% (Max).

Example 98:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Step 1: Ethyl 2-(methylthio)pyrimidine-5-carboxylate

To a stirred solution of ethyl-4-chloro-(2-methyl thio pyrimidine)5-carboxylate (10 g, 42.9 mmol) in THF/water (8:2, 100 mL), zinc powder(14.0 g, 0.21 mmol) followed by t-BuOH (2 mL) were added and theresulting mixture was heated at 90° C. for overnight. The reactioncompletion was monitored by LCMS. The mixture was filtered throughcelite and evaporated under vacuum. The crude product was dissolved indichloromethane (100 mL), washed with water (50 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep (Method B) (colorless liquid). ¹H NMR (400 MHz,DMSO-d₆): 9.03 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t,J=7.08 Hz, 3H). LCMS: (Method A) 199.0 (M+H), Rt. 3.50 min, 99.7% (Max).

Step 2: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate

To a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate(2.8 g, 14.2 mmol) in tetrahydrofuran at 0° C., 3-chloroperbenzoic acid(7.8 g, 60.7 mmol, spectrochem) was added and the resulting solution wasstirred at rt for 3 h. It was concentrated. DCM was added and was washedwith water (25 mL) and 10% sodium bicarbonate solution (20 mL) and driedover Na₂SO₄. After evaporation of the solvents, the crude product waspurified by flash chromatography to afford the titled product. Yield:50.7% (1.65 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): 9.48 (s,2H), 4.43 (q, J=7.0 Hz, 2H), 3.48 (s, 3H), 1.37 (t, J=7.1 Hz, 3H), LCMS:(Method A) 230.9 (M+H), Rt. 2.33 min, 97.48% (Max).

Step 3: Ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 2 (1.87 g, 6.94 mmol) in dryacetonitrile, potassium carbonate (2.87 g, 20.8 mmol, spectrochem) andethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate were added and theresulting mixture was at rt for 12 h. It was filtered through celite andconcentrated. Dichloromethane (25 mL) was added and the solution waswashed with water, brine and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash column chromatographyto afford the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆):8.74 (s, 2H), 6.85 (t, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 1H), 5.98 (s,2H), 4.25 (q, J=6.8 Hz, 2H), 3.81 (s, 4H), 3.32 (s, 1H), 2.37-2.42 (m,4H), 1.28 (d, J=6.6 Hz, 6H). LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min,98.88% (Max).

Step 4: Lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of ethyl2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(0.9 g, 2.34 mmol) in MeOH (2 mL), THF (7 mL) and water (1 mL) mixture,lithium hydroxide (0.24 g, 5.85 mmol, spectrochem) was added at 0° C.The resulting mixture was stirred at rt for 12 h. It was concentratedand the crude product was used without further purification. Yield: 90%(0.52 g, off white solid). LCMS: (Method A) 357.0 (M+H), Rt. 2.38 min,99.21% (Max).

Step 5:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

To a stirred solution of lithium2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(300 mg, 0.82 mmol) in dry DMF (5 mL), methyl amine (0.09 mL, 0.988mmol, 2M in THF), DIPEA (0.45 mL, 2.47 mmol) and HATU (471 mg, 1.29mmol) were added and the resulting mixture was stirred at rt for 12 h.It was concentrated under vacuum and the crude product was diluted withDCM (20 mL), washed with water (15 mL) and dried over anhydrous Na₂SO₄.After evaporation of the solvents, the crude product was purified by MDAutoprep (Method B) to give the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.71 (s, 2H), 8.29 (q, J=4.4 Hz, 1H), 6.90 (d,J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H),5.98 (m, 2H), 3.78-3.76 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.74 (d, J=4.8Hz, 3H), 2.45-2.42 (m, 2H), 2.37-2.32 (m, 2H), 1.28 (d, J=6.4 Hz, 3H).LCMS: (Method A) 370.2 (M+H), Rt. 2.24 min, 97.69% (Max). HPLC: (MethodA) Rt. 2.19 min, 99.52% (Max).

Example 99:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

The title compound was synthesized according the same protocol asExample 98, using dimethyl amine (2 M in THF) as reagent. The crudeproduct was purified by MD Autoprep (Method B) to afford the titlecompound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 2H), 6.90(d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H),5.98 (m, 2H), 3.77-3.74 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.97 (s, 6H),2.47-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS:(Method A) 384.0 (M+H), Rt. 2.51 min, 99.94% (Max). HPLC: (Method A) Rt.2.35 min, 99.85% (Max).

Example 105:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)propionamide

To a stirred solution of Example 41 (310 mg, 1.2 mmol) in dry DCM (10mL), TEA (0.4 mL, 2.78 mmol) and propionyl chloride (94 mg, 1.02 mmol)were added at 0° C. and the resulting mixture was stirred at rtovernight. The reaction mixture was concentrated under vacuum and theresulting crude product was purified by flash chromatography to give thetitle compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.96 (s,1H), 6.83 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.98(m, 2H), 3.34-3.32 (m, 5H), 2.51-2.37 (m, 6H), 1.28 (d, J=6.8 Hz, 3H),1.04 (d, J=7.2 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.57 min,99.27% (Max). HPLC: (Method A) Rt. 2.48 min, 99.7% (Max).

Example 106:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)butyramide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using butyryl chloride asacylating agent. The resulting crude product was purified by flashcolumn chromatography followed by MD Autoprep (Method B) to give thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s,1H), 6.89 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0,1.6 Hz, 1H), 5.98 (m, 2H), 3.39 (q, J=5.6 Hz, 1H), 3.35-3.33 (m, 4H),2.56-2.40 (m, 4H), 2.36 (t, J=7.6 Hz, 2H), 1.61-1.55 (m, 2H), 1.28 (d,J=6.4 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt.2.81 min, 97.58% (Max). HPLC: (Method A) Rt. 2.84 min, 99.12% (Max).

Example 107:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)isobutyramide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using isobutyryl chloride asacylating agent. The crude product was purified by flash chromatographyto give the title compound (white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.99 (s, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd,J=8.0, 1.2 Hz, 1H), 5.99 (m, 2H), 3.43 (q, J=6.8 Hz, 1H), 3.80-3.33 (m,4H), 2.72-2.65 (m, 1H), 2.44-2.32 (m, 4H), 1.28 (d, J=6.8 Hz, 3H), 1.09(d, J=6.8 Hz, 6H). LCMS: (Method A) 404.2 (M+H), Rt. 2.82 min, 98.33%(Max). HPLC: (Method A) Rt. 2.75 min, 99.73% (Max).

Example 108:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamide

The title compound was synthesized according the same protocol asdescribed for the synthesis of Example 105, using cyclopropane carbonylchloride as acylating agent. The crude product was purified by flashchromatography followed by MD Autoprep (Method B) to give the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H),6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz,1H), 5.99 (m, 2H), 3.39 (q, J=6.4 Hz, 1H), 3.33-3.28 (m, 4H), 2.56-2.39(m, 4H), 1.88-1.87 (m, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.90-0.83 (m, 4H).LCMS: (Method A) 402.2 (M+H), Rt. 2.63 min, 99.66% (Max). HPLC: (MethodA) Rt. 2.66 min, 99.76% (Max).

Example 109:2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

To a stirred solution of lithium2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate(0.7 g, 18.37 mmol, Example 62, Step 2) in dry DMF (7 mL), methyl amine(2M in THF, 1.3 mL, 27.55 mmol), HATU (0.83 g, 22.0 mmol) and DIPEA (0.9mL, 55.1 mmol) were added and the reaction mixture was stirred overnightat rt. It was cooled to rt and concentrated. Water (15 mL) was added tothe resulting mixture and was extracted with EtOAc (2×30 mL). Theorganic layer was dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by MD Autoprep HPLC (Method B)to afford the title compound as off white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.14 (q, J=4.0, 1H), 7.70 (s, 1H), 6.77-6.74 (m, 3H), 4.40(s, 4H), 3.39-3.38 (m, 5H), 2.67 (d, J=4.4 Hz, 3H), 2.49-2.48 (m, 2H),2.44-2.38 (m, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H),Rt. 2.26 min, 97.94% (Max). HPLC: (Method A) Rt. 2.23 min, 98.53% (Max).

Example 110:N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-chlorobenzamide

To a stirred solution of Example 41 (0.40 g, 1.2 mmol) in dry DCM (10mL), TEA (0.4 mL, 0.45 mmol) and 4-chlorobenzoyl chloride (0.28 g, 1.65mmol) were added at 0° C. and the resulting mixture was stirredovernight at rt. It was concentrated under vacuum and the resultingcrude product was purified by flash chromatography to give the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): 12.69 (s, 1H),8.06 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.75-6.89 (m, 3H), 5.99(t, J=0.4 Hz, 2H), 3.39-3.42 (m, 5H), 2.42-2.45 (m, 4H), 1.28 (d, J=6.80Hz, 3H), LCMS: (Method A) 471.1 (M+H), Rt. 3.59 min, 98.8% (Max). HPLC:(Method A) Rt. 3.56 min, 98.7% (Max).

Example 111:5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-(4-chlorobenzyl)-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 41 (0.3 g, 0.90 mmol) in dry1,2-dichloroethane (3 mL), titanium isopropoxide (0.8 mL, 2.71 mmol) and4-chlorobenzaldehyde (0.19 g, 1.35 mmol) were added and the reactionmixture was refluxed for 8 h. It was cooled to 0° C. and sodiumborohydride (0.17 g, 4.51 mmol) was added and the mixture was stirred atrt for 2 h. It was concentrated and water (15 mL) was added to theresulting crude product. It was extracted with EtOAc (2×30 mL). Theorganic layer was dried over anhydrous Na₂SO₄. After evaporation of thesolvents, the crude product was purified by MD Autoprep HPLC (Method B)to afford the title compound as off white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 7.58 (t, J=6.0 Hz, 1H), 7.39-7.32 (m, 4H), 6.86 (s, 1H),6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.97-6.97 (m, 2H), 4.33(m, 2H), 3.32-3.21 (m, 1H), 3.19-3.16 (m, 4H), 2.43-2.21 (m, 4H), 1.25(d, J=6.4 Hz, 3H). LCMS: (Method B) 458.0 (M+H), Rt. 6.16 min, 96.93%(Max). HPLC: (Method A) Rt. 3.21 min, 96.02% (Max).

Example 112:5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

The title compound was synthesized following the same procedure asExample 111, using acetaldehyde (0.17 mL, 1.35 mmol) as startingmaterial. After evaporation of the solvents, the crude product waspurified by flash chromatography to afford the title compound as offwhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.99 (t, J=5.2 Hz, 1H), 6.88(d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.6, 1.2 Hz, 1H),5.99-5.98 (m, 2H), 3.37 (d, J=6.4 Hz, 1H), 3.19-3.13 (m, 6H), 2.45-2.32(m, 4H), 1.25 (d, J=6.4 Hz, 3H), 1.11 (t, d, J=6.8 Hz, 3H). LCMS:(Method A) 362.0 (M+H), Rt. 2.01 min, 96.31% (Max). HPLC: (Method A) Rt.1.98 min, 94.56% (Max).

Example 128:N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 7 (0.3 g, 1.14 mmol) and Intermediate 21(0.269 g, 1.48 mmol) as starting materials. The crude product waspurified by flash chromatography (7% MeOH in DCM) followed by MDAutoprep HPLC (Method B) to give the title compound (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.76(d, J=87.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.4 Hz, 2H), 3.39-3.28 (m,5H), 3.14 (t, J=8.4 Hz, 2H), 2.42-2.39 (m, 4H), 2.09 (s, 3H), 1.28 (d,J=6.4 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.34 min, 99.62% (Max).HPLC: (Method A) Rt. 2.32 min, 96.03% (Max).

Example 129:N-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

The title compound was synthesized according the protocol used forExample 114, using Intermediate 10 (0.3 g, 1.16 mmol) and Intermediate21 (0.274 g, 1.51 mmol) as starting materials. The crude product waspurified by flash chromatography (10% MeOH in DCM) followed by MDAutoprep HPLC (Method B) to give the title compound (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (s, 1H), 8.45 (s, 2H), 7.13 (d, J=7.6Hz, 1H), 6.75-6.70 (m, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.63-3.61 (m, 4H),3.12 (t, J=8.4 Hz, 3H), 2.44-2.30 (m, 4H), 1.99 (s, 3H), 1.26 (d, J=6.4Hz, 3H). LCMS: (Method A) 368.3 (M+H), Rt. 2.34 min, 99.74% (Max). HPLC:(Method A) Rt. 2.33 min, 99.52% (Max).

Example 132:(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of Intermediate 16 (3 g, 11.1 mmol) in ACN (30mL), TEA (3.36 g, 33.3 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (2.19g, 12.2 mmol) were added at rt and the mixture was heated at 85° C.overnight. The completion of the reaction was confirmed by TLC. Thereaction mixture was evaporated under vacuum and the resulting crudesolid was diluted with water (30 mL) and extracted with EtOAc (3×30 mL).The combined organic layer was washed with brine (30 mL), dried overNa₂SO₄ and evaporated at 45° C. under vacuum. The crude product waspurified by flash chromatography (7% MeOH in DCM) to give the titlecompound (pale brown solid). ¹H NMR (400 MHz, DMSO-d6): δ 6.88-6.83 (m,2H), 6.76-6.74 (m, 1H), 6.46 (s, 2H), 5.91 (d, J=1.6 Hz, 2H), 3.39-3.37(m, 1H), 3.20-3.17 (m, 4H), 2.46-2.30 (m, 4H), 1.25 (d, J=6.5 Hz, 3H).LCMS: (Method A) 334.0 (M+H), Rt. 1.85 min, 96.47% (Max). HPLC: (MethodA) Rt. 1.79 min, 96.77% (Max). Chiral HPLC: (Method D) Rt. 20.96 min,100.00%

Example 134: (S)2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Step 1: Ethyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 16 (1.87 g, 6.94 mmol) in dryacetonitrile (10 mL), potassium carbonate (2.87 g, 20.8 mmol,Spectrochem) and ethyl 2-(methylsulfonyl) pyrimidine-5-carboxylate (1.6g, 6.94 mmol, synthesis described in Example 98, steps, 1 and 2) wereadded. The resulting mixture was stirred at rt for 3 h. It was thenfiltered through celite and concentrated. The crude product was dilutedwith dichloromethane (25 mL), washed with water and dried over anhydrousNa₂SO₄. After evaporation of the solvent, the crude product was purifiedby flash column chromatography to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 1H), 6.78-6.72 (m, 2H),5.97 (s, 1H), 4.38-4.36 (m, 1H), 3.81 (s, 2H), 2.37-2.47 (m, 9H), 1.26(d, J=2.84 Hz, 3H), LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min, 98.6%(Max).

Step 2: Lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of ethyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(1.6 g, 17.5 mmol) in a mixture of MeOH (2 mL), THF (7 mL) and water (1mL), lithium hydroxide (0.431 g, 5.20 mmol, Spectrochem) was added at 0°C. and the resulting mixture was stirred at rt for 12 h. It wasconcentrated and the resulting product was taken for next step withoutany further purification. Yield: 96% (0.61 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.61 (s, 1H), 6.81-6.88 (m, 4H), 5.97 (d, J=1.8Hz, 2H), 3.68 (d, J=6.2 Hz, 2H), 3.22-3.21 (m, 1H), 2.28-2.35 (m, 6H),1.26 (d, J=8.9 Hz, 3H), LCMS: (Method A) 357.0 (M+H), Rt. 2.41 min,97.1% (Max)

Step 3: (S)2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

To a stirred solution of lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate(0.3 g, 0.82 mmol) in dry DCM (10 mL), triethylamine (0.34 mL) andmethylamine in THF (2 M, 1.6 mL, 3.32 mmol) were added at 0° C. Thereaction mixture was stirred at rt for 1 h. The reaction progression wasmonitored by TLC. After completion of the reaction, the mixture wasdiluted with 10% sodium bicarbonate solution (10 mL) and extracted withDCM (20 mL). The organic layer was dried over Na₂SO₄ and evaporated todryness. The crude product was purified by flash column chromatography.Yield: 56% (0.17 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.71(s, 2H), 8.28 (d, J=4.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.77-6.75 (m, 1H),5.98 (d, J=2.0 Hz, 2H), 3.77 (t, J=4.8 Hz, 4H), 3.41-3.38 (m, 1H), 2.74(d, J=4.4 Hz, 3H), 2.38-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 370.2 (M+H), Rt. 2.21 min, 98.9% (Max). HPLC: (Method A) Rt.2.18 min, 99.3% (Max). Chiral HPLC: (Method G) Rt. 5.51 min, 100.00%

Example 137:(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

The title compound was synthesized using the same procedure as describedfor Example 134, using lithium(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylateand N,N-dimethyl amine as solution in THF as starting materials. Thecrude product was purified by flash column chromatography (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 2H), 6.90 (s, 1H), 6.84(d, J=8.0 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98 (d, J=1.6 Hz, 2H), 3.76(t, J=4.8 Hz, 4H), 3.39-3.37 (m, 1H), 2.97 (s, 6H), 2.44-2.43 (m, 2H),2.37-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.2 (M+H),Rt. 2.44 min, 98.2% (Max). HPLC: (Method A) Rt. 2.44 min, 98.3% (Max).Chiral HPLC: (Method G) Rt. 6.98 min, 100.00%

Example 141:(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 132 (0.7 g, 2.1 mmol) in THF (14 mL),acetaldehyde (0.84 mL, 5M in THF) and titanium(IV)ethoxide (0.958 g, 4.2mmol) were added and the resulting mixture was stirred at rt overnight.The completion of the reaction was confirmed by TLC. The reactionmixture was cooled to 0° C. and sodium borohydride (0.238 g, 6.3 mmol)was added. The reaction mixture was stirred 2 h at rt. It was quenchedwith water (10 mL) and filtered through celite. The celite bed washedwith EtOAc (2×50 mL) and the filtrate was washed with water (10 mL),brine (10 mL), dried over Na₂SO₄. It was evaporated at 50° C. undervacuum. The crude product was purified by MD Autoprep HPLC (Method D) togive the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ6.98 (t, J=5.2 Hz, 2H), 6.88 (d, J=1.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),6.75 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.37 (q, J=6.8 Hz, 2H),3.20-3.14 (m, 6H), 2.47-2.36 (m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.11 (t,J=7.2 Hz, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.01 min, 99.75% (Max).HPLC: (Method A) Rt. 2.02 min, 97.69% (Max). Chiral HPLC: (Method B) Rt.3.90 min, 100%

Example 142:(S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propyl-1,3,4-thiadiazol-2-amine

To a stirred solution of Example 132 (0.5 g, 1.5 mmol) in THF (10 mL),propionaldehyde (0.17 g, 3.0) and titanium(IV)ethoxide (0.684 g, 3.0mmol) were added at rt and stirred overnight. The completion of thereaction was confirmed by TLC. The reaction mixture was cooled to 0° C.and sodium borohydride (0.17 g, 4.4 mmol) was added. The reactionmixture was stirred for 2 h at rt. It was quenched with water (10 mL)and filtered through celite. The celite bed washed with EtOAc (2×50 mL)and the filtrate was washed with water (10 mL), brine solution (10 mL)and dried over Na₂SO₄. It was evaporated at 50° C. under vacuum. Thecrude product was purified by MD Autoprep HPLC (Method D) to give thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.02 (t,J=5.2 Hz, 2H), 6.88 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd,J=7.6, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.41 (q, J=6.4 Hz, 2H), 3.20-3.17(m, 4H), 3.11-3.06 (m, 2H), 2.45-2.32 (m, 4H), 1.56-1.47 (m, 2H), 1.26(d, J=6.4 Hz, 3H), 0.86 (t, J=7.6 Hz, 3H). LCMS: (Method A) 376.0.0(M+H), Rt. 2.23 min, 99.08% (Max). HPLC: (Method A) Rt. 2.21 min, 97.11%(Max). Chiral HPLC: (Method B) Rt. 3.61. min, 100%.

Example 144:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

Step 1: tert-Butyl 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.0 g, 4.08 mmol) in dioxane (10 mL), TEA (0.58 g,5.3 mmol) and bromo acetone (0.67 mL, 5.3 mmol) were added at rt and theresulting mixture was stirred at 90° C. for 16 h. The completion of thereaction was monitored by TLC. The reaction mixture was diluted withwater (10 mL) and extracted with EtOAc (2×25 mL). The organic layer wasdried over anhydrous Na₂SO₄, concentrated under vacuum. The crudeproduct was taken as such for next step. Yield: 77% (0.9 g, pale yellowsolid). LCMS: (Method A) 284.0 (M+H), Rt. 2.74 min, 83.2% (Max).

Step 2: 4-Methyl-2-(piperazin-1-yl)thiazole Hydrochloride

To a stirred solution of tert-butyl4-(4-methylthiazol-2-yl)piperazine-1-carboxylate (1.0 g, 3.53 mmol) indry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt and theresulting mixture was stirred for 3 h. It was concentrated under vacuumand the resulting crude product was triturated in Et₂O, filtrated anddried under vacuum to afford the title compound. Yield: 75% (500 mg, offwhite solid).

Step 3:2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

The title compound was synthesized by following general procedure D,using 4-methyl-2-(piperazin-1-yl)thiazole hydrochloride (1.01 g, 5.41mmol) and Intermediate 1 (1.0 g, 5.41 mmol). The crude product waspurified by flash chromatography (1.2-1.5% MeOH in DCM) to afford thetitle compound (colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 6.88 (s,1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.34 (s, 1H), 5.97(s, 2H), 3.39-3.37 (m, 1H), 3.32-3.29 (m, 4H), 2.46-2.43 (m, 2H),2.41-2.37 (m, 2H), 2.10 (s, 1H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (MethodA) 332.0 (M+H), Rt. 2.04 min, 99.1% (Max). HPLC: (Method A) Rt. 2.02min, 99.6% (Max).

Example 148:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediate 25 (0.75 g, 2.43 mmol) in dry DMF(7 mL), TEA (1.4 mL, 7.30 mmol) and Intermediate 1 (0.9 g, 4.87 mmol)were added at rt. The resulting mixture was stirred overnight at 120° C.It was cooled to rt and DMF was evaporated under reduced pressure.Resulting crude product was purified by flash column chromatographyfollowed by MD Autoprep HPLC (Method B), affording the title product(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.32 (s, 1H), 6.86-6.84(m, 3H), 5.99-5.98 (m, 2H), 3.45-3.44 (m, 4H), 3.38-3.34 (m, 2H),2.70-2.67 (m, 2H), 2.50-2.59 (m, 4H), 1.28-1.23 (m, 3H). LCMS: (MethodA) 387.2 (M+H), Rt. 2.15 min, 96.71% (Max). HPLC: (Method A) Rt. 2.11min, 94.32% (Max).

Example 166:(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine

To a stirred solution of Intermediate 16 (0.25 g, 0.93 mmol) in dry DMF(5 mL), TEA (0.4 mL, 2.7 mmol) and 2-chloro-5-fluoro methyl pyridine(0.16 g, 9.3 mmol) were added at rt. The resulting reaction mixture wasstirred at 90° C. for 12 h. It was cooled to rt, concentrated anddiluted with dichloromethane (30 mL). The resulting solution was washedwith saturated NaCl solution (10 mL), dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography affording the title compound (brown oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.38 (s, 1H), 7.78 (dd, J=9.2, 2.4 Hz, 1H), 6.88 (d,J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.77-6.75 (m, 1H), 5.99-5.98 (m,2H), 3.60 (t, J=4.8 Hz, 4H), 3.40-3.37 (m, 1H), 2.48-2.44 (m, 4H), 1.27(d, J=6.4 Hz, 3H). LCMS: (Method A) 380.0 (M+H), Rt. 3.73 min, 98.89%(Max). HPLC: (Method A) Rt. 3.67 min, 99.06% (Max).

Example 167:(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

Step 1: 1-(2-chloropyrimidin-5-yl)ethan-1-one

5-Bromo 2-chloro pyrimidine (2 g, 10.33 mmol, Combi-Blocks) was degassedfor 30 min. 1-Ethoxy vinyl tributyltin (4.1 mL, 11.3 mmol, FrontierScientific) and bis(triphenylphosphine)palladium dichloride (0.36 g,0.51 mmol) were added at rt. The resulting mixture was stirred overnightat 90° C. It was cooled to rt and filtered through celite. An aqueousHCl solution (6 N, 10 mL) was added and the mixture was stirred for 1hour at rt. It was neutralized with sat. NaHCO₃ solution (15 mL),extracted with DCM (50 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by flash columnchromatography to afford the title compound (pale yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.90 (s, 2H), 2.65 (s, 3H). LCMS: (Method B) 162.0(M+H), Rt. 4.6 min, 98.01% (Max).

Step 2:(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

To a stirred solution of Intermediate 16 (1.14 g, 4.24 mmol) in dry DMF(10 mL), TEA (1.1 mL, 16.5 mmol) and1-(2-chloropyrimidin-5-yl)ethan-1-one obtained in the previous step (0.6g, 3.85 mmol) were added at rt. The resulting mixture was heated to 90°C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50mL) was added and was washed with a saturated NaCl solution (10 mL),dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography, affording the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 2H), 6.90 (s, 1H),6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H),3.84 (t, J=4.8 Hz, 4H), 3.40-3.36 (m, 1H), 2.49-2.47 (m, 5H), 2.38-2.35(m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 355.0 (M+H), Rt. 2.61min, 99.78% (Max). HPLC: (Method A) Rt. 2.55 min, 99.51% (Max).

Example 168:1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

To a stirred solution of Example 167 (0.2 g, 0.56 mmol) in dry MeOH (5mL), sodium borohydride (0.48 g, 0.84 mmol, spectrochem) was addedportion wise at 0° C. The resulting mixture was stirred at rt for 1 h.It was concentrated, diluted with DCM (20 mL) and washed with brinesolution (5 mL) and dried over Na₂SO₄. After evaporation of the solvent,the crude product was purified by flash column chromatography to affordthe titled compound. Yield: 77% (0.154 g, brown oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76(dd, J=8.0, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H),4.62-4.59 (m, 1H), 3.67 (t, J=5.2 Hz, 4H), 3.39-3.37 (m, 1H), 2.42-2.40(m, 2H), 2.35-2.32 (m, 2H), 1.32-1.27 (m, 6H). LCMS: (Method A) 357.2(M+H), Rt. 2.38 min, 99.04% (Max). HPLC: (Method A) Rt. 2.31 min, 98.15%(Max).

Example 171:2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of 3-hydroxypropionic acid (97 mg, 1.0 mmol) indry NMP (5 mL), Example 132 (300 mg, 0.9 mmol), triethylamine (0.18 mg,1.8 mmol) and HATU (513 mg, 1.3 mmol) were added at 0° C. The resultingmixture was stirred at rt for 1 h. It was was diluted with water (15 mL)and extracted with EtOAc (2×15 mL). Combined organic layers was driedover Na₂SO₄. After evaporation of the solvents, the crude product wasfurther purified by MD Autoprep HPLC (Method B), affording the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ11.98 (s, 1H),6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.97(m, 2H), 4.71 (t, J=5.2 Hz, 1H), 3.69-3.64 (m, 2H), 3.40-3.32 (m, 5H),2.54-2.32 (m, 6H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 406.0 (M+H),Rt. 2.15 min, 99.05% (Max). HPLC: (Method A) Rt. 2.11 min, 98.88% (Max).

Example 173:(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-fluoropyrimidine

To a stirred solution of Intermediate 16 (0.4 g, 1.50 mmol) in dry DMF(10 mL), TEA (0.6 mL, 4.5 mmol) and 2-chloro-5-fluoro pyrimidine (0.2 g,1.5 mmol) were added at rt and the reaction mixture was stirred at 90°C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50mL) was added and the mixture was washed with sat NaCl solution (10 mL)dried over anhydrous Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography to give the titlecompound (colourless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (s, 2H),7.43 (d, J=7.6 Hz, 1H), 6.89-6.85 (m, 1H), 6.75 (dd, J=7.6, 1.2 Hz, 1H),5.99-5.98 (m, 2H), 3.65 (t, J=5.2 Hz, 4H), 3.37-3.35 (m, 1H), 2.43-2.41(m, 2H), 2.37-2.35 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A)331.0 (M+H), Rt. 2.88 min, 99.79% (Max). HPLC: (Method A) Rt. 2.82 min,99.93% (Max).

Example 175:(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-bromopyrimidine

To a stirred solution of Intermediate 16 (4.1 g, 15.5 mmol) in dry DMF(30 mL), TEA (6.4 mL, 46.5 mmol) and 5-bromo-2-chloro pyrimidine (3 g,15.5 mmol) were added at rt and the reaction mixture was stirred at 90°C. for 12 h. It was cooled to rt and concentrated under reducedpressure. Dichloromethane (150 mL) was added. The solution was washedwith brine (50 mL) and dried over anhydrous Na₂SO₄. After evaporation ofthe solvents, the crude product was purified by flash chromatographyaffording the title compound. Yield: 57% (3.5 g, white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.43 (s, 2H), 6.83-6.89 (m, 2H), 6.76 (d, J=7.8Hz, 1H), 5.99-5.98 (m, 2H), 3.67 (t, J=4.8 Hz, 4H), 3.37-3.33 (m, 1H),2.41-2.33 (m, 4H), 1.28 (d, J=6.6 Hz, 3H). LCMS: (Method A) 391.0 (M+H),Rt. 3.25 min, 99.9% (Max).

Example 176:(S)-2-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) cooled at −78° C., n-BuLi (1.6 M, 1.2 mL, 19.2 mmol, Aldrich) wasadded. The mixture was stirred at −78° C. for 1 h. Dry acetone in THF(0.89 g, 1.53 mmol, Aldrich) was then added at the same temperature andthe mixture was stirred for 10 minutes. The temperature was increased tort over 1 h. The reaction mixture was quenched with saturated ammoniumchloride solution (10 mL). The desired product was extracted with EtOAc(50 mL), washed with sat NaCl solution (20 mL) and dried over anhydrousNa₂SO₄. After evaporation of the solvents, the crude product waspurified by MD Autoprep HPLC (Method D), affording the title product(off white solid). ¹H NMR (400 MHz, DMSO-d₆): 8.33 (s, 2H), 6.89-6.83(m, 2H), 6.77-6.74 (m, 1H), 5.99-5.98 (m, 2H), 5.05 (s, 1H), 3.66 (d,J=4.8 Hz, 4H), 3.38-3.35 (m, 1H), 2.45-2.43 (m, 2H), 2.35-2.32 (m, 2H),1.59 (s, 6H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt.2.5 min, 99.51% (Max). HPLC: (Method A) Rt. 2.46 min, 98.9% (Max).

Example 177:(S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

Step 1:(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

To a stirred solution of Intermediate 16 (4.8 g, 18.7 mmol) in dry ACN(15 mL), Et₃N (10.5 mL, 75.0 mmol) and 2-chloro-5-nitropyrimidine (3.0g, 18.7 mmol) were added at rt. The mixture was heated at 80° C.overnight. It was cooled to rt, diluted with DCM (20 mL), washed withwater (15 mL) and brine (15 mL), and dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the crude product was triturated with MeOH,filtered and dried under vacuum, affording the title compound. Yield:75% (3.8 g, pale yellow solid). LCMS: (Method A) 358.3 (M+H), Rt. 2.94min, 98.07% (Max).

Step 2:(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

To a stirred solution of(S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidineobtained in the previous step (1.0 g, 62.9 mmol) in a mixture ofmethanol (100 mL) and THF (100 mL), 10% Pd/C (200 mg, 20% w/w) was addedat rt. The reaction mixture was stirred under hydrogen atmosphere (1kg/cm²) at rt overnight. Completion of the reaction was confirmed byTLC. The reaction mixture was filtered through celite and washed withmethanol. After evaporation of the solvents, the title compound wasobtained and used in the next step without further purification. Yield:96% (1.0 g, pale brown solid). LCMS: (Method A) 328.2 (M+H), Rt. 1.52min, 90.58% (Max).

Step 3:(S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

To a stirred solution of 3-hydroxypropionic acid (132 mg, 1.0 mmol) indry DMF (2 mL),(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amineobtained in the previous step (400 mg, 1.2 mmol), DIPA (236 mg, 1.83mmol) and HATU (557 mg, 1.83 mmol) were added at 0° C. The reactionmixture was stirred at rt overnight. The completion of the reaction wasmonitored by TLC. The reaction mixture was diluted water (10 mL) andextracted with DCM (15 mL). The organic layer was dried over anhydrousNa₂SO₄ and evaporated. The crude product was purified by preparativeHPLC (Method B), affording the title product (off white solid). ¹H NMR(400 MHz, CDCl₃): δ 8.40 (s, 2H), 7.79 (br s, 1H), 6.88 (s, 1H), 6.75(s, 2H), 5.96-5.95 (m, 2H), 3.97 (t, J=6.8 Hz, 2H), 3.77 (t, J=4.8 Hz,4H), 3.35 (q, J=6.8 Hz, 1H), 2.56-2.62 (m, 2H), 2.48-2.55 (m, 2H),2.42-2.51 (m, 2H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 400.2 (M+H),Rt. 2.11 min, 99.42% (Max). HPLC: (Method A) Rt. 2.06 min, 98.9% (Max).

Example 180:(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclohexan-1-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) at −78° C., n-BuLi (1.6M, 0.9 mL, 15.3 mmol, Aldrich) was added andthe reaction mixture was stirred at −78° C. for 1 h. Cyclohexanone (0.15g, 1.53 mmol, Aldrich) in dry THF (1 mL) was added at −78° C. and themixture was stirred for 10 minutes. The temperature was increased to rtover 1 h. The reaction completion was monitored by TLC. The reaction wasquenched with saturated ammonium chloride solution (10 mL) and wasextracted with EtOAc (50 mL). The organic layer was washed with sat NaClsolution (20 mL) dried over anhydrous Na₂SO₄ and the solvents wereevaporated under reduced pressure. The crude product was purified byflash column chromatography to afford the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83(d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.73 (s,1H), 3.65-3.63 (m, 4H), 3.33-3.31 (m, 1H), 2.40-2.38 (m, 2H), 2.34-2.32(m, 2H), 1.65-1.60 (m, 6H), 1.45-1.42 (m, 2H), 1.28-1.22 (m, 5H). LCMS:(Method A) 411.2 (M+H), Rt. 3.25 min, 96.51% (Max). HPLC: (Method A) Rt.3.14 min, 97.88% (Max).

Example 181:(S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclopentan-1-ol

The title compound was prepared according to the protocol described forthe preparation of Example 180, replacing cyclohexanone withcyclopentanone (0.12 g, 1.53 mmol, Aldrich). The crude product waspurified by flash column chromatography to afford the title compound(brown oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 6.88 (s, 1H),6.83 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.80(s, 1H), 3.65-3.63 (m, 4H), 3.32-3.30 (m, 1H), 2.49-2.45 (m, 2H),2.34-2.32 (m, 2H), 1.82-1.7 (m, 8H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 397.2 (M+H), Rt. 2.90 min, 98.83% (Max). HPLC: (Method A) Rt.2.87 min, 99.10% (Max).

Example 183: Ethyl(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

To a stirred solution of Intermediate 16 (1.0 g, 3.71 mmol) in dry DMF(10 mL), TEA (1.54 mL, 11.1 mmol) and ethyl-6-chloro nicotinate (0.69 g,3.71 mmol) were added at rt and the reaction mixture was heated at 90°C. for 12 h. It was cooled to rt and concentrated. DCM (50 mL) was addedand the resulting solution was washed with brine (30 mL) and dried overanhydrous Na₂SO₄. After evaporation of the solvents, the crude productwas purified by flash chromatography to give the title compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.4 Hz, 1H),7.92-7.90 (m, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.85-6.81 (m, 2H), 6.77-6.75(m, 1H), 5.99-5.98 (m, 2H), 4.27 (q, J=7.2 Hz, 2H) 3.61 (t, J=4.8 Hz,4H), 3.39-3.37 (m, 1H), 2.45-2.33 (m, 5H), 1.29-1.26 (m, 3H). LCMS:(Method A) 384.2 (M+H), Rt. 3.14 min, 98.30% (Max). HPLC: (Method A) Rt.3.11 min, 98.88% (Max).

Example 185:(S)-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)methanol

To a stirred solution of Example 183 (0.2 g, 0.56 mmol) in dry MeOH (5mL) cooled at 0° C., was added lithium aluminium hydride (2.4 M, 0.24mL, 1.17 mmol, spectrochem) dropwise and the mixture was stirred for 1 hat the same temperature. The reaction mixture was quenched withsaturated ammonium chloride (5 mL) and extracted with ethyl acetate (20mL). The organic phase was washed with brine solution (5 mL), dried overNa₂SO₄ and concentrated. The crude product was purified by flash columnchromatography to afford the titled compound. Yield: 66% (88 mg,colorless oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (d, J=2.0 Hz, 1H),7.46 (dd, J=8.8, 2.4 Hz, 1H), 6.88-6.86 (m, 1H), 6.84-6.82 (m, 1H),6.76-6.73 (m, 2H), 5.98-5.97 (m, 2H), 4.96 (t, J=5.6 Hz, 1H) 4.32 (d,J=5.6 Hz, 2H), 3.41 (t, J=9.6 Hz, 4H), 3.34-3.32 (m, 1H), 2.49-2.45 (m,2H), 2.39-2.37 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 342.3(M+H), Rt. 1.74 min, 99.28% (Max). HPLC: (Method A) Rt. 1.71 min, 98.49%(Max).

Example 186:(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

Step 1: Lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

Example 183 (1 g, 2.62 mmol) was dissolved in a mixture of MeOH (2 mL),THF (7 mL) and water (1 mL). The resulting mixture was cooled to 0° C.and lithium hydroxide (0.32 g, 7.86 mmol, spectrochem) was added. Theresulting mixture was heated at 90° C. for 2 h. It was then concentratedand used as such in next step. Yield: 85% (0.8 g, off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.52 (d, J=2.3 Hz, 1H), 7.89-7.86 (m, 1H),6.88-6.59 (m, 4H), 5.97-5.96 (m, 2H), 3.43-3.33 (m, 5H), 2.36-2.28 (m,4H), 1.26 (d, J=8.7 Hz, 3H). LCMS: (Method A) 354.0 (M+H), Rt. 3.639min, 93.32% (Max).

Step 2:(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

To a stirred solution of lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate(0.3 g, 8.32 mmol) in dry DCM (10 mL) cooled to 0° C., were addedtriethylamine (0.5 mL, 3.72 mmol), methylamine in THF (2 M, 2 mL, 2.24mmol) followed by T₃P (0.6 mL, 3.72 mmol). The resulting mixture wasstirred at rt for 1 h. Reaction completion was monitored by TLC. Thereaction mixture was washed with 10% sodium bicarbonate solution (10mL). The organic layer was dried over Na₂SO₄, and evaporated to dryness.The crude product was purified by flash column chromatography (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.54 (d, J=2.0 Hz, 1H), 8.18 (d,J=4.4 Hz, 1H), 7.89 (dd, J=2.4, 9.2 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H),6.85-6.77 (m, 1H), 6.77-6.74 (m, 2H), 5.99-5.98 (m, 2H), 3.54 (t, J=4.8Hz, 4H), 3.37-3.35 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.45-2.43 (m, 2H),2.39-2.32 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 369.2 (M+H),Rt. 2.05 min, 98.6% (Max). HPLC: (Method A) Rt. 2.00 min, 98.3% (Max).

Example 187:(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylnicotinamide

To a stirred solution of lithium(S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate(Example 186, Step 1, 0.5 g, 1.38 mmol) in dry DCM (10 mL) at 0° C.,were added triethylamine (2.6 mL, 4.14 mmol), dimethylamine in THF (2 M,2 mL, 2.24 mmol) followed by T₃P (2.6 mL, 4.14 mmol). The resultingmixture was stirred at rt for 1 h. Reaction completion was monitored byTLC. The reaction mixture was washed with 10% sodium bicarbonatesolution (10 mL). The organic layer was dried over Na₂SO₄, andevaporated to dryness. The crude product was purified by flash columnchromatography. Yield: 52% (279 mg, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.19 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.4, 8.8 Hz, 1H), 6.90(s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.78 (t, J=7.2 Hz, 2H), 5.99-5.98 (m,2H), 3.54-3.51 (m, 4H), 3.38-3.33 (m, 1H), 2.96 (s, 6H), 2.47-2.46 (m,2H), 2.41-2.34 (m, 2H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 383.3(M+H), Rt. 2.19 min, 99.8% (Max). HPLC: (Method A) Rt. 2.14 min, 99.6%(Max).

Example 188:(S)-4-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10mL) at −78° C. was added n-BuLi (1.6 M, 1.2 mL, 1.92 mmol, Aldrich) andthe resulting mixture was stirred to −78° C. for 1 h.Tetrahydrofuran-4H-pyran-4-one (0.15 g, 1.53 mmol, Aldrich) in THF (5mL) was added at −78° C. for 10 minutes. The temperature was increasedto rt over 1 h. The reaction completion was monitored by TLC. Thereaction mixture was quenched with saturated ammonium chloride solution(10 mL). It was extracted with EtOAc (50 mL). The organic phase waswashed with saturated NaCl solution (20 mL) and dried over anhydrousNa₂SO₄. The crude product was purified by flash column chromatography toafford the title compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆):δ 8.42 (s, 2H), 6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz,1H), 5.99-5.98 (m, 2H), 5.07 (s, 1H), 3.77-3.66 (m, 8H), 3.39-3.37 (m,1H), 2.44-2.40 (m, 2H), 2.37-2.33 (m, 2H), 1.95-1.87 (m, 2H), 1.57-1.54(m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 413.3 (M+H), Rt. 2.32min, 99.65% (Max). HPLC: (Method A) Rt. 2.27 min, 99.23% (Max).

Example 189:3-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydrofuran-3-ol

Example 189 was prepared according the same procedure as Example 188,replacing tetrahydrofuran-4H-pyran-4-one with dihydrofuran(2H)-one (0.13g, 1.53 mmol, Aldrich). The crude product was purified by flash columnchromatography to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.41 (s, 2H), 6.90 (d, J=1.2 Hz, 1H), 6.84 (d,J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.97-3.93 (m,2H), 3.78-3.76 (m, 1H), 3.68-3.65 (m, 6H), 2.50-2.42 (m, 1H), 2.35-2.32(m, 4H), 2.33-2.32 (m, 1H), 2.11-2.06 (m, 1H), 1.28 (d, J=6.4 Hz, 3H).LCMS: (Method A) 399.0 (M+H), Rt. 2.32 min, 97.39% (Max). HPLC: (MethodA) Rt. 2.22 min, 97.15% (Max).

Example 190:(S)-2-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol

To a stirred solution of Example 183 (0.3 g, 0.78 mmol) in dry THF (10mL) at 0° C. was added methyl magnesium bromide solution in THF (1.4 M,0.8 mL, 1.17 mmol, Aldrich). The resulting mixture was stirred at 0° C.for 1 h. The temperature was increased to rt and the mixture was stirred12 h at that temperature. The reaction completion was monitored by TLC.The reaction mixture was quenched with saturated ammonium chloridesolution (10 mL) and extracted with EtOAc (50 mL). The organic layer waswashed with sat NaCl solution (20 mL) and dried over anhydrous Na₂SO₄.The crude product was purified by flash column chromatography, yieldingthe title compound. Yield: 61% (0.178 g, colorless oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.17 (d, J=2.0 Hz, 1H), 7.59-7.57 (m, 1H), 6.89-6.83(m, 2H), 6.78-6.70 (m, 2H), 5.99-5.98 (m, 2H), 4.92 (s, 1H), 3.39 (t,J=4.8 Hz, 5H), 2.40-2.36 (m, 4H), 1.39 (s, 6H), 1.29 (d, J=6.8 Hz, 3H).LCMS: (Method A) 370.2 (M+H), Rt. 1.94 min, 99.3% (Max). HPLC: (MethodA) Rt. 1.92 min, 99.60% (Max).

Example 191:(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-bromopyridin-2-yl)piperazine

To a stirred solution of Intermediate 16 (5.5 g, 20.68 mmol) in dry DMF(50 mL), TEA (7.1 mL, 51.45 mmol) and 5-bromo-2-fluoropyridine (3 g,17.24 mmol) were added at rt and the reaction mixture was stirred at 90°C. overnight. The reaction mixture was cooled to rt and concentratedunder reduced pressure. Water (30 mL) was added and the compound wasextracted with EtOAc (100 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The resulting crude product waspurified by flash chromatography to afford the title compound (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (d, J=2.4 Hz, 1H), 7.66-7.65(m, 1H), 6.87 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.77-6.55 (m,2H), 5.99-5.98 (m, 2H), 3.43 (t, J=4.8 Hz, 4H), 3.36-3.34 (m, 1H),2.47-2.45 (m, 2H), 2.38-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS:(Method A) 392.0 (M+H), Rt. 3.32 min, 99.88% (Max). HPLC: (Method A) Rt.3.26 min, 99.96% (Max).

Example 192:(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(methylthio)pyridin-2-yl)piperazine

To a stirred solution of Example 191 (3.0 g, 7.71 mmol) in dry THF (30mL), n-BuLi (6.0 mL, 9.2 mmol) was added at −78° C. and stirred for 1 h.Dimethyl disulphide (45 mL) was added at same temperature and stirredfor 1 h at rt. The reaction mixture was quenched with saturated NH₄Cland extracted with EtOAc. The organic layer was washed with water anddried over anhydrous Na₂SO₄ and concentrated. The resulting crude waspurified by flash column chromatography to afford the title compound.Yield: 90% (2.58 g, yellow solid). ¹H NMR (400 MHz, CDCl₃): δ 8.21 (d,J=2.4 Hz, 1H), 7.52-7.51 (m, 1H), 6.89 (s, 1H), 6.76 (s, 2H), 6.56 (d,J=8.8 Hz, 1H), 5.96-5.94 (m, 2H), 3.52 (m, 4H), 3.34 (d, J=6.0 Hz, 1H),2.57-2.50 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 358.3.0 (M+H), Rt. 2.61 min, 97.99% (Max). HPLC: (Method A) Rt. 2.56min, 97.57% (Max).

Example 195:(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-methoxypyrimidine

To a stirred solution of Intermediate 16 (0.55 g, 2.07 mmol) in dry DMF(5 mL), triethylamine (0.9 mL, 6.21 mmol, spectrochem) and2-chloro-5-methoxy pyrimidine (0.3 g, 2.07 mmol, Combi-Blocks) wereadded and the resulting mixture was heated to 90° C. for 12 h. Thereaction mixture was cooled down to rt and concentrated. Dichloromethane(25 mL) was added and the resulting solution was washed with water (20mL), brined (20 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash column chromatographyto afford the title compound (brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.18 (s, 2H), 6.87 (m, 2H), 6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H),3.76 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.38-3.36 (m, 1H), 2.45-2.42 (m,2H), 2.36-2.33 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.2(M+H), Rt. 2.73 min, 99.83% (Max). HPLC: (Method A) Rt. 2.71 min, 99.41%(Max).

Example 197 and 198:(S)-1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-oland(S)-1-(2-(4-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

Example 168 was submitted to chiral preparative HPLC Method PK toseparate both enantiomers. The first eluting compound was concentratedto give Example 198 (brown oil). ¹H NMR (400 MHz, DMSO d₆): δ 8.29 (s,2H), 6.89 (s, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H),5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.62-4.61 (m, 1H), 3.67-3.65(m, 4H), 3.38-3.36 (m, 1H), 2.51-2.33 (m, 4H), 1.31 (d, J=6.4 Hz, 3H),1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.30 min,99.37% (Max). HPLC: (Method A) Rt. 2.30 min, 98.05% (Max). Chiral HPLC:(Method H) Rt. 7.06 min, 100%. The second eluting compound wasconcentrated to give Example 197 (brown oil). ¹H NMR (400 MHz, DMSO d₆):δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz,1H), 5.99-5.98 (m, 2H), 5.11 (d, J=4.4 Hz, 1H), 4.62-4.59 (m, 1H),3.68-3.65 (m, 4H), 3.38-3.36 (m, 1H), 2.35-2.32 (m, 4H), 1.31 (d, J=6.4Hz, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.29min, 99.93% (Max). HPLC: (Method N) Rt. 2.26 min, 99.62% (Max). ChiralHPLC: (Method H) Rt 7.60 min, 100%.

Example 199:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediates 25 (0.5 g, 1.61 mmol) in DMF (5mL, 10V), TEA (0.89 mL, 6.4 mmol) and Intermediate 21 (0.44 g, 2.41mmol) were added at rt and the mixture was stirred at 80° C. for 12 h.It was concentrated under vacuum and resulting crude mixture waspurified by MD Autoprep HPLC (Method C) to afford titled compound (offwhite solid). ¹H NMR (400 MHz, DMSO-d6): δ 7.29 (s, 1H), 7.16 (d, J=7.2Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H),3.46-3.42 (m, 4H), 3.38-3.36 (m, 4H), 3.14 (t, J=8.8 Hz, 2H), 2.69 (t,J=7.2 Hz, 2H), 2.44-2.43 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (MethodA) 358.0 (M+H), Rt. 2.324 min, 97.963% (Max). HPLC: (Method A) Rt. 2.279min, 99.224% (Max).

Example 200: Ethyl5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate

To a stirred solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate(0.25 g, 1.29 mmol) in dry DMF (2.5 mL), K₂CO₃ (0.54 g, 3.89 mmol) andIntermediate 30 (0.59 g, 1.93 mmol) were added at rt. The reactionmixture was stirred overnight at 80° C. It was then concentrated undervacuum. EtOAc (10 mL) was added and the resulting solution was washedwith water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography toafford the title compound. Yield: 51% (0.26 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.15 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H),6.71 (s, 1H), 4.50 (t, J=8.80 Hz, 2H), 4.33 (q, J=6.80 Hz, 2H), 3.54 (t,J=5.20 Hz, 4H), 3.43-3.41 (m, 1H), 3.13 (t, J=8.40 Hz, 2H), 2.45-2.32(m, 4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H), Rt. 2.88 min,95.7% (Max). HPLC: (Method A) Rt 2.81 min, 96.5% (Max).

Example 201:5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methyl-1,3,4-thiadiazole-2-carboxamide

The title compound was synthesized according to the procedure describedfor Example 59 and 60, starting from Example 200 (brown thick oil). ¹HNMR (400 MHz, DMSO-d₆): δ 8.74 (q, J=4.8 Hz, 1H), 7.16 (d, J=7.2 Hz,1H), 6.76 (d, J=1.2 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.40 Hz, 2H), 3.49(t, J=4.80 Hz, 4H), 3.43-3.41 (m, 1H), 3.14 (t, J=8.80 Hz, 2H), 2.75 (d,J=4.8 Hz, 3H), 2.53-2.51 (m, 2H), 2.46-2.42 (m, 2H), 1.28 (d, J=6.8 Hz,3H). LCMS: (Method A) 374.0 (M+H), Rt. 2.35 min, 96.4% (Max). HPLC:(Method A) Rt 2.30 min, 98.2% (Max).

Examples 202 and 203:(R)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideand(S)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The racemic mixture of Example 128 was separated by SFC using thepreparative chiral method PA.

The first eluting compound correspond to Example 202 (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 11.99 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75(d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.38-3.36 (m,1H), 3.35-3.33 (m, 4H), 3.13 (t, J=8.4 Hz, 2H), 2.42-2.38 (m, 4H), 2.07(s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31min, 99.4% (Max). HPLC: (Method A) Rt 2.34 min, 99.7% (Max). CHIRALHPLC: (SFC Method AA) Rt. 2.81 min, 100% (Max).

The second eluting compound corresponds to Example 203 (white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75(d, J=7.6 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.37-3.36 (m,1H), 3.32-3.31 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.41-2.38 (m, 4H), 2.08(s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31min, 99.37% (Max). HPLC: (Method A) Rt 2.35 min, 99.59% (Max). CHIRALHPLC: (SFC Method AA) Rt. 3.45 min, 99.42% (Max).

Example B01: Human O-GlcNAcase Enzyme Inhibition Assay

5 μl of the appropriate concentration of a solution of inhibitor inMcIlvaine's Buffer (pH 6.5) in 2% DMSO (for a dose response curvecalculation) is added into each well of a 384-well plate (Greiner,781900). Then, 20 nM of His-Tagged hOGA and 10 μM of FL-GlcNAc(Fluorescein mono-beta-D-(2-deoxy-2-N-acetyl) glucopyranoside; MarkerGene Technologies Inc, M1485) were added to the 384-well plate for afinal volume of 20 μl. After incubation for 60 min at room temperature,the reaction was terminated by the addition of 10 μL of stop buffer (200mM glycine, pH 10.75). The level of fluorescence (λ_(exc) 485 nm;(λ_(emm) 520 nm) was read on a PHERAstar machine. The amount offluorescence measured was plotted against the concentration of inhibitorto produce a sigmoidal dose response curve to calculate an IC₅₀. Allindividual data was corrected by subtraction of the background (Thiamet3 uM=100% inhibition) whilst 0.5% DMSO was considered as the controlvalue (no inhibition).

Example B02: Pharmacodynamic Model: Total Protein O-GlcNAcylationImmunoassay (RL2 mAb, Meso Scale Electrochemiluminescence (ECL) Assay)

The test compound was administered orally to C57BL/6J mice. At definedtime intervals after compound administration, typically a time rangingbetween 2 and 48 hours, preferably between 4 and 24 hours, mice weresacrificed by decapitation for blood collection and forebraindissection. Right brain hemispheres were placed in 2 ml Precellys tubes,snap frozen in dry ice and stored at −80° C. Left hemispheres wereplaced in 2 ml Eppendorf tubes, snap frozen in dry ice and stored at−80° C. until further processing. Blood samples were collected inSarstedt tubes containing 35 IU of Heparin and kept at 4° C. Aftercentrifugation for 10 min at 3800×g, 4° C., 50 μL of plasma from eachsample was transferred to a 1.5 ml Eppendorf tube and stored at −80° C.

For the preparation of soluble brain protein for the immunoassay thehemispheres were homogenized in ice-cold Cytobuster reagent (71009—MerckMillipore) buffer with protease inhibitor cocktail. After centrifugationfor 15 min at 17000×g at 4° C. the supernatants were transferred intopolycarbonate tubes (1 ml). The supernatants were cleared bycentrifugation for 1 h. at 100000×g, 4° C., and the proteinconcentrations were determined by using the BCA kit (23227—Pierce,Rockford, Ill.) according to the manufacturer's instructions.

Total Protein O-GlcNAcylation Immunoassay:

Samples were randomised and 120 μg/ml (25 μl/well) of soluble brainprotein was directly coated on a Multi-array 96-well high bind plate(L15XB-3 High bind—Meso Scale Discovery) overnight at 4° C. Afterwashing (3× with PBS-T buffer), the plate was blocked with MSD blocker Asolution for 1 h. at room temperature (RT) under agitation. Afterwashing (3× with PBS-T buffer), the plate was incubated with 0.1 μg/mlof a mouse monoclonal antibody directed against O-GlcNAc moieties (RL2;MA1-072—Thermo Scientific) for 1 h. at RT under agitation. For the ECLassay, after washing (3× with PBS-T buffer), 1 μg/ml of a SULFO-TAG™labeled anti-mouse secondary antibody (Meso Scale Discovery) was addedand the plate was incubated for 1 h. at RT under agitation and protectedfrom light. After washing (3× with PBS-T buffer), 150 μl/well of 1× ReadBuffer T was added to the plates before reading on a Sector Imager 6000(Meso Scale Discovery).

Example B03: Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bi-distilled water was adjusted to pH 6.5 using 2 N hydrochloricacid, sterile filtered, transferred into injection vials, lyophilizedunder sterile conditions and sealed under sterile conditions. Eachinjection vial contained 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention was melted with 100 g of soy lecithin and 1400 g ofcocoa butter, poured into moulds and allowed to cool. Each suppositorycontained 20 mg of active ingredient.

(C) Solution: A solution was prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g ofNa₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbi-distilled water. The pH was adjusted to 6.8, and the solution wasmade up to 1 l and sterilized by irradiation. This solution could beused in the form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionwere mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate was pressed to give tablets in aconventional manner in such a way that each tablet contained 10 mg ofactive ingredient.

(F) Coated tablets: Tablets were pressed analogously to EXAMPLE E andsubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionwere introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contained 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bi-distilled water was sterile filtered,transferred into ampoules, lyophilized under sterile conditions andsealed under sterile conditions. Each ampoule contained 10 mg of activeingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention were dissolved in 10 l of isotonic NaCl solution, and thesolution was transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14mg.

Example C01: Physical Properties Characterization Methods

X-Ray Powder Diffraction (XRPD)

Approximately 5-10 mg of sample was gently compressed on the XRPD zeroback ground single obliquely cut silica sample holder. The sample wasthen loaded into a Philips X-Pert PRO diffractometer and analysed usingthe following experimental conditions.

-   -   Tube anode: Cu    -   Generator tension: 40 kV    -   Tube current: 40 mA    -   Wavelength alpha1: 1.5406 Å    -   Wavelength alpha2: 1.5444 Å    -   Start angle [2 theta]: 5    -   End angle [2 theta]: 50    -   Continuous scan

For suspected novel salts a slower scan speed was also used over a rangeof 4-40° 2q.

Raman Spectroscopy

Samples were analysed by a Nicolet Almega XR Dispersive Raman Microscopefor its Raman spectrum using the following conditions:

-   -   Exposure Time: 1.0 s    -   Acquisition No: 50    -   Slit Size: 100 μm    -   Wavelength range: 2000˜400 cm⁻¹ (single grating)    -   Laser: He—Ne 780 nm 100% power    -   Objective: 20×/0.40 (magnifier/numerical aperture number)

Baseline subtraction was performed on the Raman spectra. NuclearMagnetic

Resonance (NMR)

The ¹H NMR was run in DMSO-d6 using a Bruker Avance III 400 instrument.

Simultaneous Thermal Analysis (STA)

Approximately 5 mg of sample was accurately weighed into a ceramiccrucible and it was placed into the chamber of Perkin-Elmer STA 6000TGA/DTA analyzer at ambient temperature. The sample was then heated at arate of 10° C./min, typically from 30° C. to 300° C., during which timethe change in weight was monitored as well as DTA signal. The purge gasused was nitrogen at a flow rate of 20 cm³/min.

Differential Scanning calorimetry (DSC)

Approximately, 5 mg of each sample was weighed into an aluminium DSC panand sealed non-hermetically with an aluminium lid. The sample was thenloaded into a Perkin-Elmer Jade DSC and held at 30° C. Once a stableheat-flow response was obtained, the sample was then heated to a 250 or300° C. at a scan rate of 10° C./min and the resulting heat flowresponse was monitored. A 20 cm³/min helium purge was used. Prior toanalysis, the instrument was temperature and heat flow verified using anindium standard.

Example C02: Primary Salt Screen Procedure

Preferred compound of Structure I were selected for primary salt screenprocedure.

If the respective acid was a solid (such as but not limited to maleicacid, fumaric acid, succinic acid, L-tartaric acid, citric acid, adipicacid, benzoic acid, p-toluene sulphonic acid), the Compound of formula(I) (˜30 mg) was weighed into twelve separate vials with ˜1.1equivalents of the counter-ion as a physical solid mixture. 300 μL ofthe appropriate solvent was added.

If the respective acid, was in aqueous solution or a liquid (such as butnot limited to 5M hydrochloric acid, 6M sulphuric acid, 85%orthophosphoric acid, methane sulphonic acid) the appropriate volumecorresponding to ˜1.1 equivalents was added to ˜30 mg of the API in theappropriate solvent (300 μL) (mostly suspension).

The mixture was shaken well by hand. All slurries or solutions weretemperature-cycled between ambient and 40° C. for ˜18-24 hours. Ifenough solid was present the supernatant was decanted off, if possible,and the solid dried by evaporation. If a solution was observed, thesolvent was allowed to evaporate under nitrogen then dried.

Diverse solvents or solvents mixture were selected for the primary saltscreen, such as but not limited to methanol, acetone, ethyl acetate,acetonitrile, tetrahydrofuran, toluene, 50/50 methanol/water and 90/10propan-2-ol/water. They were selected on the basis of structuraldiversity and acceptability. They were all commonly used in final stepprocesses.

Any solids were examined by XRPD and are reported in FIGS. 1 to 6.

Example C03: Methods of Preparation Example C03-1: Hydrochloride SaltPreparation

A preferred method of preparation of this salt was as follows:

Compound of Formula I (1.33 mmol) was suspended in ethanol (5 mL). 5MHydrochloric acid (300 μL, 1.5 mmol, 1.25 equiv) was added and mixedwell. The resulting suspension was temperature-cycled between 40° C. andambient temperature overnight (18-24 hours). The product amassed andethanol (2 mL) was added to mobilise before the product was filtered,washed with ethanol (2×2 mL) and dried in a vacuum oven at 50° C. for˜24 hours to constant weight. (Yield 88%).

Starting from 500 mg of Example 69, 480 mg of hydrochloride salt wasobtained.

Example 69 hydrochloride salt was characterized by XRPD (FIG. 11), Raman(FIG. 12), ¹H NMR (FIG. 13), STA (FIG. 14) and DSC (FIG. 15).

Example C03-2: Maleate Salt Preparation

A preferred method of preparation of this salt was as follows:

Compound of Formula I (1.33 mmol) was suspended in ethanol (5 mL).Maleic acid (170 mg, 1.46 mmol, 1.1 equiv) was added and mixed well. Theresulting suspension was temperature-cycled between 40° C. and ambienttemperature overnight (18-24 hours). The product was filtered, washedwith ethanol (2×2 mL) and dried in a vacuum oven at 50° C. for ˜24 hoursto constant weight.

Starting from 500 mg of Example 69, 518 mg of maleate salt was obtained.

Example 69 maleate salt was characterized by XRPD (FIG. 16), ¹H NMR(FIG. 17), STA (FIG. 18) and DSC (FIG. 19).

Example C03-3: L-Tartrate Salt Preparation

A preferred method of preparation of this salt was as follows:

Compound of Formula I (1.33 mmol) was suspended in ethanol (5 mL).L-tartaric acid (200 mg, 1.33 mmol, 1 equiv) was added and mixed well.The resulting suspension was temperature-cycled between 40° C. andambient temperature overnight (18-24 hours). The product was filtered,washed with ethanol (2×2 mL) and dried in a vacuum oven at 50° C. for˜24 hours to constant weight.

Starting from 500 mg of Example 69, 599 mg of L-tartrate salt wasobtained.

Example 69 L-tartrate salt was characterized by XRPD (FIG. 20), ¹H NMR(FIG. 21).

Example C04: Visual Aqueous Solubility

The salts and free base (˜10 mg) were weighed into glass vials and waterwas added in 0.1 mL portions up to 3 mL and 1 mL portions thereafter.Solubility was assessed visually following a brief period ofequilibration.

The aqueous solubility of different salt of Example 69 was assessed, asreported in Table 1.

Example 69 Salts Visual aqueous solubility L-Tartrate salt  ~20 mg/mLMaleate salt ~4.5 mg/mL Hydrochloride salt ~4.5 mg/mL Free base  <0.5mg/mL

Salts of compounds of formula I with various other acids did not yield auseful improvement of aqueous solubility over the free base and/or havenot been stable or solid or have other properties not suitable forpharmaceutical development, especially for solid oral dosage forms, suchas tablets, e.g compressed tablets.

The invention claimed is: 1.N-(5-{4-[(1S)-1-(2H-1,3-benzodioxol-5-yl)ethyl]piperazin-1-yl}-1,3,4-thiadiazol-2-yl)acetamide,mono-hydrochloride in a solid form having the characteristic X-raypowder diffraction pattern as shown on FIG.
 11. 2. A solid oral dosageform comprising an acid addition salt according to claim 1.